Ginger | University of Maryland Medical Center

Overview

Ginger, the "root" or the rhizome, of the plant Zingiber officinale, has been a popular spice and herbal medicine for thousands of years. It has a long history of use in Asian, Indian, and Arabic herbal traditions. In China, for example, ginger has been used to help digestion and treat stomach upset, diarrhea, and nausea for more than 2,000 years. Ginger has also been used to help treat arthritis, colic, diarrhea, and heart conditions.

It has been used to help treat the common cold, flu-like symptoms, headaches, and painful menstrual periods.

Ginger is native to Asia where it has been used as a cooking spice for at least 4,400 years.

Ginger is a knotted, thick, beige underground stem, called a rhizome. The stem sticks up about 12 inches above ground with long, narrow, ribbed, green leaves, and white or yellowish-green flowers.

Researchers think the active components of the ginger root are volatile oils and pungent phenol compounds, such as gingerols and shogaols.

Today, health care professionals may recommend ginger to help prevent or treat nausea and vomiting from motion sickness, pregnancy, and cancer chemotherapy. It is also used to treat mild stomach upset, to reduce pain of osteoarthritis, and may even be used in heart disease.

Several studies, but not all, suggest that ginger may work better than placebo in reducing some symptoms of motion sickness. In one trial of 80 new sailors who were prone to motion sickness, those who took powdered ginger had less vomiting and cold sweats compared to those who took placebo. Ginger did not reduce their nausea, however. A study with healthy volunteers found the same thing.

However, other studies found that ginger does not work as well as medications for motion sickness. In one small study, people were given either fresh root or powdered ginger, scopolamine, a medication commonly prescribed for motion sickness, or a placebo. Those who took scopolamine had fewer symptoms than those who took ginger. Conventional prescription and over-the-counter medicines for nausea may also have side effects that ginger does not, such as dry mouth and drowsiness.

Human studies suggest that 1g daily of ginger may reduce nausea and vomiting in pregnant women when used for short periods (no longer than 4 days). Several studies have found that ginger is better than placebo in relieving morning sickness.

In a small study of 30 pregnant women with severe vomiting, those who took 1 gram of ginger every day for 4 days reported more relief from vomiting than those who took placebo. In a larger study of 70 pregnant women with nausea and vomiting, those who got a similar dose of ginger felt less nauseous and did not vomit as much as those who got placebo. Pregnant women should ask their doctors before taking ginger and not take more than 1g per day.

A few studies suggest that ginger reduces the severity and duration of nausea, but not vomiting, during chemotherapy. However, one of the studies used ginger combined with another anti-nausea drug. So it is hard to say whether ginger had any effect. More studies are needed.

Research is mixed as to whether ginger can help reduce nausea and vomiting following surgery. Two studies found that 1g of ginger root before surgery reduced nausea as well as a leading medication. In one of these studies, women who took ginger also needed fewer medications for nausea after surgery. But other studies have found that ginger did not help reduce nausea. In fact, one study found that ginger may actually increase vomiting following surgery. More research is needed.

Traditional medicine has used ginger for centuries to reduce inflammation. And there is some evidence that ginger may help reduce pain from osteoarthritis (OA). In a study of 261 people with OA of the knee, those who took a ginger extract twice daily had less pain and needed fewer pain-killing medications than those who received placebo. Another study found that ginger was no better than ibuprofen (Motrin, Advil) or placebo in reducing symptoms of OA. It may take several weeks for ginger to work.

Preliminary studies suggest that ginger may lower cholesterol and help prevent blood from clotting. That can help treat heart disease where blood vessels can become blocked and lead to heart attack or stroke. Other studies suggest that ginger may help improve blood sugar control among people with type 2 diabetes. More research is needed to determine whether ginger is safe or effective for heart disease and diabetes.

Ginger products are made from fresh or dried ginger root, or from steam distillation of the oil in the root. You can find ginger extracts, tinctures, capsules, and oils. You can also buy fresh ginger root and make a tea. Ginger is a common cooking spice and can be found in a variety of foods and drinks, including ginger bread, ginger snaps, ginger sticks, and ginger ale.

Pediatric

DO NOT give ginger to children under 2.

Children over 2 may take ginger to treat nausea, stomach cramping, and headaches. Ask your doctor to find the right dose.

Adult

In general, DO NOT take more than 4 g of ginger per day, including food sources. Pregnant women should not take more than 1 g per day.

The use of herbs is a time-honored approach to strengthening the body and treating disease. However, herbs can trigger side effects and interact with other herbs, supplements, or medications. For these reasons, herbs should be taken under the supervision of a health care provider, qualified in the field of botanical medicine.

It is rare to have side effects from ginger. In high doses it may cause mild heartburn, diarrhea, and irritation of the mouth. You may be able to avoid some of the mild stomach side effects, such as belching, heartburn, or stomach upset, by taking ginger supplements in capsules or taking ginger with meals.

People with gallstones should talk to their doctors before taking ginger. Be sure to tell your doctor if you are taking ginger before having surgery or being placed under anesthesia.

Pregnant or breastfeeding women, people with heart conditions, and people with diabetes should not take ginger without talking to their doctors.

DO NOT take ginger if you have a bleeding disorder or if you are taking blood-thinning medications, including aspirin.

Ginger may interact with prescription and over-the-counter medicines. If you take any of the following medicines, you should not use ginger without talking to your health care provider first.

Blood-thinning medications: Ginger may increase the risk of bleeding. Talk to your doctor before taking ginger if you take blood thinners, such as warfarin (Coumadin), clopidogrel (Plavix), or aspirin.

Diabetes medications: Ginger may lower blood sugar. That can raise the risk of developing hypoglycemia or low blood sugar.

High blood pressure medications: Ginger may lower blood pressure, raising the risk of low blood pressure or irregular heartbeat.

Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 2008;46(2):409-20.

Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001;44(11):2531-2538.

Apariman S, Ratchanon S, Wiriyasirivej B. Effectiveness of ginger for prevention of nausea and vomiting after gynecological laparoscopy. J Med Assoc Thai. 2006;89(12):2003-9.

Bliddal H, Rosetzsky A, Schlichting P, et al. A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis. Osteoarthritis Cartilage. 2000;8:9-12.

Bone ME, Wilkinson DJ, Young JR, McNeil J, Charlton S. Ginger root -- a new antiemetic. The effect of ginger root on postoperative nausea and vomiting after major gynaecological surgery. Anaesthesia. 1990;45(8):669-71.

Bordia A, Verma SK, Srivastava KC. Effect of ginger (Zingiber officinale Rosc.) and fenugreek (Trigonella foenumgraecum L.) on blood lipids, blood sugar, and platelet aggregation ion patients with coronary heart disease. Prostaglandins Leukot Essent Fatty Acids. 1997;56(5):379-384.

Chaiyakunapruk N. The efficacy of ginger for the prevention of postoperative nausea and vomiting: a meta-analysis. Am J Obstet Gynecol. 2006;194(1):95-9.

Eberhart LH, Mayer R, Betz O, et al. Ginger does not prevent postoperative nausea and vomiting after laparoscopic surgery. Anesth Analg. 2003;96(4):995-8, table.

Ernst E, Pittler MH. Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials. B J Anaesth. 2000;84(3):367-371.

Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 1991 Jan 4;38(1):19-24.

Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation, and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. J Nutr. 2000;130(5):1124-1131.

Gonlachanvit S, Chen YH, Hasler WL, et al. Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins. J Pharmacol Exp Ther. 2003;307(3):1098-1103.

Gregory PJ, Sperry M, Wilson AF. Dietary supplements for osteoarthritis. Am Fam Physician. 2008 Jan 15;77(2):177-84. Review.

Grontved A, Brask T, Kambskard J, Hentzer E. Ginger root against seasickness: a controlled trial on the open sea. Acta Otolaryngol. 1988;105:45-49.

Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000;57(13):1221-1227.

Kalava A, Darji SJ, Kalstein A, Yarmush JM, SchianodiCola J, Weinberg J. Efficacy of ginger on intraoperative and postoperative nausea and vomiting in elective cesarean section patients. Eur J Obstet Gynecol Reprod Biol. 2013;169(2):184-8.

Langner E, Greifenberg S, Gruenwald J. Ginger: history and use. Adv Ther. 1998;15(1):25-44.

Larkin M. Surgery patients at risk for herb-anaesthesia interactions. Lancet. 1999;354(9187):1362.

Lee SH, Cekanova M, Baek SJ. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Mol Carcinog. 2008;47(3):197-208.

Mahady GB, Pendland SL, Yun GS, et al. Ginger (Zingiber officinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori. Anticancer Res. 2003;23(5A):3699-3702.

Nurtjahja-Tjendraputra E, Ammit AJ, Roufogalis BD, et al. Effective anti-platelet and COX-1 enzyme inhibitors from pungent constituents of ginger. Thromb Res. 2003;111(4-5):259-265.

Phillips S, Ruggier R, Hutchinson SE. Zingiber officinale (ginger) -- an antiemetic for day case surgery. Anaesthesia. 1993;48(8):715-717.

Pongrojpaw D, Somprasit C, Chanthasenanont A. A randomized comparison of ginger and dimenhydrinate in the treatment of nausea and vomiting in pregnancy. J Med Assoc Thai. 2007 Sep;90(9):1703-9.

Portnoi G, Chng LA, Karimi-Tabesh L, et al. Prospective comparative study of the safety and effectiveness of ginger for the treatment of nausea and vomiting in pregnancy. Am J Obstet Gynecol. 2003;189(5):1374-1377.

Sripramote M, Lekhyananda N. A randomized comparison of ginger and vitamin B6 in the treatment of nausea and vomiting of pregnancy. J Med Assoc Thai. 2003;86(9):846-853.

Thomson M, Al Qattan KK, Al Sawan SM, et al. The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids. 2002;67(6):475-478.

Vaes LP, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence. Ann Pharmacother. 2000;34(12):1478-1482.

Viljoen E, Visser J, Koen N, Musekiwa A. A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutr J. 2014; 13:20.

Vutyavanich T, Kraisarin T, Ruangsri R. Ginger for nausea and vomiting in pregnancy: randomized, double-masked, placebo-controlled trial. Obstet Gynecol. 2001;97(4):577-582.

Wang CC, Chen LG, Lee LT, et al. Effects of 6-gingerol, an antioxidant from ginger, on inducing apoptosis in human leukemic HL-60 cells. In Vivo. 2003;17(6):641-645.

White B. Ginger: an overview. Am Fam Physician. 2007;75(11):1689-91.

Wigler I, Grotto I, Caspi D, et al. The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis. Osteoarthritis Cartilage. 2003;11(11):783-789.

Willetts KE, Ekangaki A, Eden JA. Effect of a ginger extract on pregnancy-induced nausea: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2003;43(2):139-144.

African ginger; Black ginger; Jamaican ginger; Zingiber officinale

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch)

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. 1997-2013 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

Read more here:
Ginger | University of Maryland Medical Center

Stem Cell Treatment UK – Stem Cell Therapy Clinic

Get In Touch

Over 60 disabling illnesses including , neurological , organ damage , metabolic disorders , blood disorders , arthiritis.... please read more for extensive list

See what people say about their personal improvements , and experiences whilst in our worldwide clinics

See my own story unfold , after recieving life changing treatment in dec 2015 watch how i improve over the coming weeks and months

Welcome to my site promoting Stemcell Treatment for UK and worldwide residents. Having been to a private clinic and experiencing drastic improvements to my own health, I want to let more people know about stemcells and that there is HOPE, to end many disabling conditions that we are led to believe are inevitably going to get worse. By contacting me I will help you to find the right treatment for your individual needs, at a clinic in a country where you will be treated as a distinguished guest, at a price more affordable than you will expect. I can speak from experience, and will gladly guide you through the whole process. Please explore my site and hit the contact me button! That much is free, and to feel better is truly miraculous!

Groundbreaking modern technology has brought us a completely natural, drugfree way to heal the

human body. Our primary task is to use your own unique stem cells to treat your own body. Using

advanced medical knowledge we can now activate dormant cells (adipose mesenchymal stem cells ) to

differentiate into the cells we need, and then they can replace the damaged cells . Symtoms become less

obvious and disappear, giving relief, and the chance to regain a normal functioning body.

See the article here:
Stem Cell Treatment UK - Stem Cell Therapy Clinic

JCI – Welcome

BACKGROUND. Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males.

METHODS. We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours.

RESULTS. Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin.

CONCLUSIONS. Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics Committee: 11/LO/2038.

FUNDING. The authors were funded by multiple sources, including the National Institute for Health Research, the British Heart Foundation, and the European Research Council.

Krishnaraj S. Rathod, Vikas Kapil, Shanti Velmurugan, Rayomand S. Khambata, Umme Siddique, Saima Khan, Sven Van Eijl, Lorna C. Gee, Jascharanpreet Bansal, Kavi Pitrola, Christopher Shaw, Fulvio DAcquisto, Romain A. Colas, Federica Marelli-Berg, Jesmond Dalli, Amrita Ahluwalia

Read the rest here:
JCI - Welcome

Sickle-cell disease – Wikipedia

Sickle-cell disease (SCD) is a group of blood disorders typically inherited from a person's parents.[1] The most common type is known as sickle-cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances.[1] Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle-cell crisis"), anemia, bacterial infections, and stroke.[2]Long term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.[1]

Sickle-cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent.[3] Several subtypes exist, depending on the exact mutation in each haemoglobin gene.[1] An attack can be set off by temperature changes, stress, dehydration, and high altitude.[2] A person with a single abnormal copy does not usually have symptoms and is said to have sickle-cell trait.[3] Such people are also referred to as carriers.[4] Diagnosis is by a blood test and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.[5]

The care of people with sickle-cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication.[4][6] Other measures may include blood transfusion, and the medication hydroxycarbamide (hydroxyurea).[6] A small proportion of people can be cured by a transplant of bone marrow cells.[1]

As of 2013 about 3.2 million people have sickle-cell disease while an additional 43 million have sickle-cell trait.[7] About 80% of sickle-cell disease cases are believed to occur in sub-Saharan Africa.[8] It also occurs relatively frequently in parts of India, the Arabian peninsula, and among people of African origin living in other parts of the world.[9] In 2013, it resulted in 176,000 deaths, up from 113,000 deaths in 1990.[10] The condition was first described in the medical literature by the American physician James B. Herrick in 1910.[11][12] In 1949 the genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954 the protective effect against malaria of sickle-cell trait was described.[12]

Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.[13]

The terms "sickle-cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD results in anemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis, and others. Most episodes of sickle-cell crises last between five and seven days.[14] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[15]

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or naproxen. For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis[16] or lungs are considered an emergency and treated with red-blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.[17]

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.[18] It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This spleen damage increases the risk of infection from encapsulated organisms;[19][20] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 12 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 34 hours and may last for one day.[21]

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.[22] It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS.[23][24] Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them.[25] Parvovirus infection almost completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.[26]

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency.[27] Management is supportive, sometimes with blood transfusions.[17]

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle-cell trait.[28] The crisis can last up to a month.[29] Another recognised type of sickle crisis, acute chest syndrome, is characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions.[30] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.[citation needed]Hematopoietic ulcers may also occur.[31]

Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.[citation needed]

Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of having sickle-cell trait. When both parents have sickle-cell trait, a child has a 25% chance of sickle-cell disease, 25% do not carry any sickle-cell alleles, and 50% have the heterozygous condition.[32]

Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[33]

In people heterozygous for HgbS (carriers of sickling haemoglobin), the polymerisation problems are minor, because the normal allele is able to produce over 50% of the haemoglobin. In people homozygous for HgbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. The sickle-cell disease occurs when the sixth amino acid, glutamic acid, is replaced by valine to change its structure and function; as such, sickle-cell anemia is also known as E6V. Valine is hydrophobic, causing the haemoglobin to collapse on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses on itself the red blood cells become sickle-shaped.[citation needed]

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the -globin gene, which results in glutamic acid (E/Glu) being substituted by valine (V/Val) at position 6. Note, historic numbering put this glutamic acid residue at position 6 due to skipping the methionine (M/Met) start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, from a GAG to GTG codon on the coding strand, which is transcribed from the template strand into a GUG codon. Based on genetic code, GAG codon translates to glutamic acid (E/Glu) while GUG codon translates to valine (V/Val) amino acid at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic side chain of the valine residue at position 6 of the beta chain in haemoglobin is able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates.

The allele responsible for sickle-cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.[34]

Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East.[35] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[36]

The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (selection for the heterozygote).

In the USA, with no endemic malaria, the prevalence of sickle-cell anaemia among African Americans is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle-cell mutation is purely disadvantageous and tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of several African and non-African ethnic groups and also represents the descendants of survivors of slavery and the slave trade. Thus, a lower degree of endogamy and, particularly, abnormally high health-selective pressure through slavery may be the most plausible explanations for the lower prevalence of sickle-cell anaemia (and, possibly, other genetic diseases) among African Americans compared to West Africans. Another factor that limits the spread of sickle-cell genes in North America is the absence of cultural proclivities to polygamy, which allows affected males to continue to seek unaffected children with multiple partners.[37]

The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction.[38] Healthy red blood cells typically function for 90120 days, but sickled cells only last 1020 days.[39]

In HbSS, the complete blood count reveals haemoglobin levels in the range of 68g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)the two most common formscan be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[40]

An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.[41]

People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle-cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.[42]

Folic acid daily for life is recommended. From birth to five years of age, penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses is also recommended.

The protective effect of sickle-cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. It has therefore been recommended that people with sickle-cell disease living in malarial countries should receive anti-malarial chemoprophylaxis for life.[43]

Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that doctors frequently prescribe to help control itching associated with the use of opioids.[citation needed]

Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),[44] oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood. The patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission.[22]

The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 (Charache et al.)[45] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[46] This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.[13][47]

Blood transfusions are often used in the management of sickle-cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBC) that can sickle by adding normal red blood cells.[48] In children preventative red blood cell (RBC) transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow.[6] In those who have sustained a prior stroke event it also reduces the risk of recurrent stroke and additional silent strokes.[49][50]

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD.[51] However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation.

About 90% of people survive to age 20, and close to 50% survive beyond the fifth decade.[52] In 2001, according to one study performed in Jamaica, the estimated mean survival for people with sickle-cell was 53 years old for men and 58 years old for women with homozygous SCD.[53] The specific life expectancy in much of the developing world is unknown.[54]

Sickle-cell anaemia can lead to various complications, including:

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle-East.[67] Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle-cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis.[68] In 2013 it resulted in 176,000 deaths due to SCD up from 113,000 deaths in 1990.[10]

Sickle-cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle-cell allele (trait) confers a selective advantagein other words, being a heterozygote is advantageous. Specifically, humans with one of the two alleles of sickle-cell disease show less severe symptoms when infected with malaria.[69]

Three-quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 12% on the north African coast and <1% in South Africa.[70] There have been studies in Africa that show a significant decrease in infant mortality rate, ages 216 months, because of the sickle-cell trait. This happened in predominant areas of malarial cases.[71]

The number of people with the disease in the United States is approximately 1 in 5,000, mostly affecting Americans of Sub-Saharan African descent, according to the National Institutes of Health.[72] In the United States, about one out of 500 African-American children and one in every 36,000 Hispanic-American children have sickle-cell anaemia.[73] It is estimated that sickle-cell disease affects 90,000 Americans.[74] Most infants with SCD born in the United States are now identified by routine neonatal screening. As of 2016 all 50 states include screening for sickle cell disease as part of their newborn screen.[75]

As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle-cell disease has become a major health problem in France.[76] SCD has become the most common genetic disease in the country, with an overall birth prevalence of 1/2,415 in mainland France, ahead of phenylketonuria (1/10,862), congenital hypothyroidism (1/3,132), congenital adrenal hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for the same reference period. In 2010, 31.5% of all newborns in mainland France (253,466 out of 805,958) were screened for SCD (this percentage was 19% in 2000). 341 newborns with SCD and 8,744 heterozygous carriers were found representing 1.1% of all newborns in mainland France. The Paris metropolitan district (le-de-France) is the region that accounts for the largest number of newborns screened for SCD (60% in 2010). The second largest number of at-risk is in Provence-Alpes-Cte d'Azur at nearly 43.2% and the lowest number is in Brittany at 5.5%.[77][78]

In the United Kingdom (UK) it is thought that between 12,000 and 15,000 people have sickle cell disease [79] with an estimate of 250,000 carriers of the condition in England alone. As the number of carriers is only estimated, all newborn babies in the UK receive a routine blood test to screen for the condition.[80] Due to many adults in high-risk groups not knowing if they are carriers, pregnant women and both partners in a couple are offered screening so they can get counselling if they have the sickle cell trait.[81] In addition blood donors from those in high-risk groups are also screened to confirm whether they are carriers and whether their blood filters properly.[82] Donors who are found to be carriers are then informed and their blood, while often used for those of the same ethnic group, is not used for those with sickle cell disease who require a blood transfusion.[83]

In Saudi Arabia about 4.2% of the population carry the sickle-cell trait and 0.26% have sickle-cell disease. The highest prevalence is in the Eastern province where approximately 17% of the population carry the gene and 1.2% have sickle-cell disease.[84] In 2005 in Saudi Arabia a mandatory pre-marital test including HB electrophoresis was launched and aimed to decrease the incidence of SCD and thalassemia.[85]

In Bahrain a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease.[86] The country began screening of all pregnant women in 1992 and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to get married to undergo free premarital counseling. These programs were accompanied by public education campaigns.[87]

Sickle-cell disease is common in ethnic groups of central India who share a genetic linkage with African communities,[citation needed] where the prevalence has ranged from 9.4 to 22.2% in endemic areas of Madhya Pradesh, Rajasthan and Chhattisgarh.[88] It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower incidence of malaria despite living in a malaria infested zone.[89]

In Jamaica, 10% of the population carries the sickle-cell gene, making it the most prevalent genetic disorder in the country.[90]

The first modern report of sickle-cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key findings was the absence of the spleen.[91][92] There were also reports amongst African slaves in the United States exhibiting resistance to malaria but being prone to leg ulcers.[92] The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (18771959), intern to the Chicago cardiologist and professor of medicine James B. Herrick (18611954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia.[11][93] Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.[11][12] Shortly after the report by Herrick, another case appeared in the Virginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia."[94] This article is based on a patient admitted to the University of Virginia Hospital on November 15, 1910.[95] In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used.[12][96] Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.[92]

The Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although it took until 1949 until the genetic characteristics were elucidated by James V. Neel and E.A. Beet.[12] 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself.[12][97] The actual molecular change in HbS was described in the late 1950s BY Vernon Ingram.[12] The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.[12]

Large scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to widespread use of prophylaxis against pneumococcal infections amongst other interventions. Bill Cosby's Emmy-winning 1972 TV movie, To All My Friends on Shore, depicted the story of the parents of a child suffering from sickle-cell disease.[98] The 1990s saw the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.[12]

Some old texts refer to it as drepanocytosis.[citation needed]

In December 1998, researchers from Emory University conducted an experimental bone marrow transplant procedure on a group of 22 children under 16 years old.[99] One of those patients, 12-year-old Keone Penn, was apparently the first person to be cured of sickle-cell disease through this method.[100] The stem cells were sourced from a donor unrelated to Penn. A 2007 Georgia Senate bill proposing the collection and donation of stem cell material, the "Saving the Cure Act", was nicknamed "Keone's Law" in his honor.[101]

By mid-2007 a similar set of clinical trials in Baltimore had also cured several adults.[102]

In 2001 it was reported that sickle-cell disease had been successfully treated in mice using gene therapy.[103][104] The researchers used a viral vector to make the micewhich have essentially the same defect that causes human sickle cell diseaseexpress production of fetal haemoglobin (HbF), which an individual normally ceases to produce shortly after birth. In humans, using hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate sickle cell disease symptoms. The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production.[105]

Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector-modified bone marrow for adults with severe sickle cell disease.[106][107] As of 2014, however, no randomized controlled trials have been reported.[108]

Originally posted here:
Sickle-cell disease - Wikipedia

Adult Stem Cells and Regeneration | HHMI BioInteractive

Mature organisms have stem cells of various sorts, called adult stem cells. Adult stem cells supply cells that compensate for the loss of cells from normal cell death and turnover, such as the ever-dying cells of our skin, our blood, and the lining of our gut. They are also an essential source of cells for healing and regeneration in response to injury. Some animals, such as sea stars, newts, and flatworms, are capable of dramatic feats of regeneration, producing replacement limbs, eyes, or most of a body. It is an evolutionary puzzle why mammals have more limited powers of regeneration.

Researchers are interested in pinpointing where adult stem cells reside and in understanding how flexible adult stem cells are in their ability to produce divergent cells such as muscle and red blood cells. Understanding the sources and the rules for the differentiation of adult stem cells is essential for tapping their therapeutic potential. Since consenting adults can provide adult stem cells, some people think that adult stem cells may be a less controversial area of research than embryonic stem cells.

Continue reading here:
Adult Stem Cells and Regeneration | HHMI BioInteractive

Stem Cells Market – Global Industry Analysis, Size, Share …

Table of Content

Chapter 1 Preface

1.1 Report Description

1.2 Research Methodology

Chapter 2 Executive Summary

Chapter 3 Market Overview

3.1 Market Trends and Future Outlook

3.1.1 Global Stem Cells Market, 2010 2018 (USD Billion)

3.2 Market Dynamics

3.2.1 Market Drivers

3.2.1.1 Unmet Medical Needs

3.2.1.2 Increasing Government Support

3.2.1.3 Growing Medical Tourism

3.2.1.4 Rising Stem Cells Banking Services

3.2.1.5 Impact Analysis of the Market Drivers

3.2.2 Market Restraints

3.2.2.1 High Cost of Treatment

3.2.2.2 Government Regulations against Unethical Harvesting of Stem Cells

3.2.2.3 Impact Analysis of the Market Restraints

3.2.3 Market Opportunities

3.2.3.1 Rising Neurodegenerative Disease Patients

3.2.3.2 Increasing Disposable Income in Emerging Nations

3.2.3.3 Replacing Animal Tissue in Drug Discovery

3.2.3.4 Growing Contract Research Industry

3.2.4 Porters Five Forces Analysis for the Global Stem Cells Market

3.2.4.1 Bargaining Power of Suppliers

3.2.4.2 Bargaining Power of Buyers

3.2.4.3 Threat of New Entrants

3.2.4.4 Threat of Substitutes

3.2.5 Competitive Rivalry

3.3 Market Attractiveness

3.3.1 Market Attractiveness Analysis of the Global Stem Cells Market, By Geography

Chapter 4 Global Stem Cells Market, By Products

4.1 Market Segmentation: Global Stem Cells Market, By Products

4.2 Overview

4.3 Adult Stem Cells Market, 2010 2018 (USD Billion)

4.3.1 Hematopoietic Stem Cells Market, 2010 2018 (USD Billion)

4.3.2 Mesenchymal Stem Cells Market, 2010 2018 (USD Billion)

4.3.3 Neuronal Stem Cells Market, 2010 2018 (USD Billion)

4.3.4 Dental Stem Cells (Mesenchymal Stem Cells, Neuronal Stem Cells) Market, 2010 2018 (USD Billion)

4.3.5 Umbilical Cord Stem Cells (Hematopoietic Stem Cells, Mesenchymal Stem Cells) Market, 2010 2018 (USD Billion)

4.4 Human Embryonic Stem Cells Market, 2010 2018 (USD Billion)

4.5 Induced Pluripotent Stem Cells Market, 2010 2018 (USD Billion)

4.6 Rat Neural Stem Cells Market, 2010 2018 (USD Billion)

4.7 Very Small Embryonic-Like Stem Cells Market, 2010 2018 (USD Billion)

Chapter 5 Global Stem Cells Market, By Technology

5.1 Market Segmentation: Global Stem Cells Market, By Technology

5.2 Overview

5.3 Global Stem Cell Acquisition Market, 2010 2018 (USD Billion)

5.3.1 Global Bone Marrow Harvest for Stem Cells, 2010 2018 (USD Billion)

5.3.2 Global Apheresis for Stem Cells Market, 2010 2018 (USD Billion)

5.3.3 Global Umbilical Cord Blood Market, 2010 2018 (USD Billion)

5.4 Global Stem Cell Production Market, 2010 2018 (USD Billion)

5.4.1 Global Therapeutic Cloning for Stem Cells Market, 2010 2018 (USD Billion)

5.4.2 Global Stem Cells Production By In Vitro Fertilization Market, 2010 2018 (USD Billion)

5.4.3 Global Stem Cell Isolation Market, 2010 2018 (USD Billion)

5.4.4 Global Stem Cell Culture Market, 2010 2018 (USD Billion)

5.5 Global Stem Cell Cryopreservation Market, 2010 2018 (USD Billion)

5.6 Global Stem Cells Expansion and Sub-Culture Market, 2010 2018 (USD Billion)

Chapter 6 Global Stem Cells Market, By Application

6.1 Market Segmentation: Global Stem Cells Market, By Application

6.2 Overview

6.3 Global Stem Cells Market in Regenerative Medicine, 2010 2018 (USD Billion)

6.3.1 Stem Cells Market in Neurology, 2010 2018 (USD Billion)

6.3.2 Global Stem Cells Market in Orthopedics, 2010 2018 (USD Billion)

6.3.3 Global Stem Cells Market in Oncology, 2010 2018 (USD Billion)

6.3.4 Global Stem Cells Market in Hematology, 2010 2018 (USD Billion)

6.3.5 Global Stem Cells Market for Cardiovascular and Myocardial Infarction, 2010 2018 (USD Billion)

6.3.6 Global Stem Cells Market for Injuries, 2010 2018 (USD Billion)

6.3.6.1 Global Stem Cells Market for Wound Care, 2010 2018 (USD Billion)

6.3.6.2 Global Stem Cells Market for Spinal Cord Injuries, 2010 2018 (USD Billion)

6.3.6.3 Global Stem Cells Market for Other (Joint Injuries, Eye Injuries, Lacerations and Concussions) Injuries, 2010 2018 (USD Billion)

6.3.7 Global Stem Cells Market for Diabetes, 2010 2018 (USD Billion)

6.3.8 Global Stem Cells Market for Liver Disorders, 2010 2018 (USD Billion)

6.3.9 Global Stem Cells Market for Incontinence, 2010 2018 (USD Billion)

6.3.10 Global Stem Cells Market for Other (Crohns Disease, Infertility, Immunodeficiency Disorder, Organ Transplants, Ophthalmic Disorder) Regenerative Medicine Applications, 2010 2018 (USD Billion)

6.4 Global Stem Cells Market in Drug Discovery and Development, 2010 2018 (USD Billion)

Chapter 7 Global Stem Cells Market, By Geography

7.1 Overview

7.2 North America

7.2.1 North America Stem Cells Market, 20102018 (USD Billion)

7.3 Europe

7.3.1 Europe Stem Cells Market, 20102018 (USD Billion)

7.4 Asia

7.4.1 Asia Stem Cells Market, 20102018 (USD Billion)

7.5 Rest of the World (Row)

7.5.1 Row Stem Cells Market, 20102018 (USD Billion)

Chapter 8 Competitive Landscape

8.1 Heat Map Analysis for the Key Market Players

8.1.1 Advanced Cell Technology Inc.

8.1.2 STEMCELL Technologies Inc.

8.1.3 Cellular Engineering Technologies Inc.

See the original post here:
Stem Cells Market - Global Industry Analysis, Size, Share ...

Treatment for Chronic Obstructive Pulmonary Disease Dallas

Chronic Obstructive Lung Disease (COPD) is a debilitating lung condition that leaves patients unable to breathe or enjoy life. It is also known as emphysema, chronic bronchitis and chronic obstructive asthma. COPD is rated as the third leading killer in the United States, killing approximately 120,000 individuals a year. Persons suffering from COPD also experience chronic disability and often a low quality of life. Sufferers also require a large amount of medical care with its expense and the need to stay near medical facilities and personnel. COPD is a very limiting and deadly disease.

This paper is designed to help readers gain a greater understanding of the use of adult stem cells for COPD and offer a framework for evaluating if stem cell treatment is a potential step for you or your loved one. We will cover the following:

Feel free to skip to sections that provide information that is helpful to you.

For more information including definitions and descriptions of COPD visit: http://www.lung.org/lung-disease/copd/ http://www.mayoclinic.com/health/copd/DS00916

Skip to next section

COPD is a chronic condition and therefore typically requires long term medications. The commonly used treatment options are:

With the exception of surgery, these treatment options are all considered supportive. They help the symptoms but do not change the underlying disease. A simplified diagram of these treatments is:

A COPD patient may be prescribed one, several or all of these at one time or another during the course of their illness. Some patients suffer without using any treatments. The effectiveness of treatment varies greatly both between patients and over the course of the illness. Many patients with COPD do very well for many years with exercise with or without medications.

For more information on the treatment of COPD see: http://www.lung.org/lung-disease/copd/living-with-copd/copd-management-tools.html or http://www.guideline.gov/content.aspx?id=23801

If you are a person doing well using these options, this might not be the right time to consider adult stem cell treatment.

Skip to next section

If you are doing well with your current medical therapy, you may not be an ideal candidate for adult stem cell therapy. Persons should consider adult stem cell therapy for COPD include:

Lung changes in COPD

Adult stem cell therapy DOES NOT assure a response in these patients. However, it does offer an alternative that they may wish to consider. We will discuss results below.

Skip to next section

All stem cells, no matter their source, share two important characteristics:

When we obtain stem cells from mature adult tissues they are referred to as adult stem cells. As with all stem cells, the potential exists for adult stem cells to become any type of cell and then make new copies of the new cell type. This ability to become any type of cell and then make as many cells as needed is the reason for so much interest in adult stem cells. We refer to the process of obtaining adult stem cells as harvesting. To be a good tissue for harvesting, a tissue should be easy to harvest and have an abundant number of stem cells. The two tissues that most readily meet these requirements are bone marrow and fat.

Adult stem cells taken from fat are also known as adipose derived adult stem cells. Stem cells from fat have become increasingly attractive because stem cells from fat are easier to obtain and exist in larger numbers than bone marrow adult stem cells.

For more information on stem cells visit:

What are stem cellsor California Stem Cell Center

Skip to next section

It is a simple process to harvest adult stem cells from fat. First we select an area to take the fat like the stomach or leg. The area is marked and sterilized. Next a local anesthetic solution is injected into the area through a small incision. Suction is applied using a syringe with a special tool called a cannula attached. Typically 50 ml (about 1 1.2 oz.) of fat is suctioned for processing.

There can be some swelling and /or bruising after the harvesting procedure. Swelling and bruising typically resolve in about 2-3 weeks. Patients are given a prescription for pain medications in case they need them. An antibiotic is given before the procedure. Since the procedure is done sterilely, no further antibiotics are needed. Applying ice to the harvest area for a few days after the procedure reduces the swelling and bruising.

After harvesting we take the fat and do some simple processing to isolate the adult stem cells. When finished, the final product is called Stromal Vascular Fraction (SVF). SVF is a very powerful mixture of adult stem cells and growth factors. Growth factors are the chemical messengers our bodies use to promote healing and cell growth. Growth factors have sometimes been referred to as text messages between cells. A typical batch of SVF contains up to about 25 million adult stem cells. Each SVF batch also contains a large amount of growth factors. The growth factors harvested in SVF tend to be highly anti-inflammatory. After harvesting and processing the SVF is now ready to be deployed for your COPD. It can also be used for many other disorders. A number of deployment protocols under investigation for a large number of disorders.

For more about the harvesting process please visit: Harvesting adult stem cells

Skip to next section

We refer to the process of actually using the adult stem cells/SVF ( Stromal Vascular Fraction ) as deployment. The typical deployment for COPD is intravenous. We also nebulize a small amount of the stme cells/SVF and have the patient inhale it.

The IV is started in the office and the stem cells/SVF is injected into a small IV bag. This is then given to the patient over 20-30 minutes. The nebulizer is given during the time the IV is running. When the nebulizer and IV are finished, the IV is discontinued and the patient is discharged.

Skip to next section

Although research is in progress, there are currently no treatment groups large enough to answer this question conclusively. It is important to be aware that the Food and Drug Administration (FDA) has NOT approved the use of adult stem cells/SVF ( Stromal Vascular Fraction ) for any disorder including COPD. Understanding these issues, we do have enough experience to talk about early trends in therapy.

Around 90% of patients respond to deployment with adult stem cells/SVF. The most common response is an increase in exercise ability. Patients feel they can walk further without becoming winded. Patients also note an increase in their oxygen saturation levels (O2 sat). Most patients respond to only one deployment. Some require a repeat deployment in 3-6 months.

This is one of the most common questions asked by our adult stem cell/SVF ( Stromal Vascular Fraction ) patients. Response to deployment for COPD varies from a few days to about 3 months. If a patient has not seen a significant improvement after about 3 months, we recommend a repeat deployment. Many patients continue to see improvement for several months. When they plateau or regress, we then consider a repeat deployment for them as well.

Most of the time repeat deployment is done after the patient has seen some improvement and more improvement is sought. Occasionally, repeat deployment is done because the patient has lost some improvement previously seen. The question of how many deployments are best and how often they are needed is an area of intense interest and study at this time. It is too early to say conclusively that adult stem cells treatment promotes the growth of new lung cells.

We hope we have answered the majority of your questions. If you have others or wish to schedule a consultation please call: 214-420-7970.

Follow this link:
Treatment for Chronic Obstructive Pulmonary Disease Dallas

Breast Cancer Research | Home page

Dr. Lewis A. Chodosh is a physician-scientist who received a BS in Molecular Biophysics and Biochemistry from Yale University, and MD from Harvard Medical School, and a PhD. in Biochemistry from M.I.T. in the laboratory of Dr. Phillip Sharp.He performed his clinical training in Internal Medicine and Endocrinology at the Massachusetts General Hospital, after which he was a postdoctoral research fellow with Dr. Philip Leder at Harvard Medical School.Dr. Chodosh joined the faculty of the University of Pennsylvania in 1994, where he is currently a Professor in the Departments of Cancer Biology, Cell & Developmental Biology, and Medicine. He serves as Chairman of the Department of Cancer Biology, Associate Director for Basic Science of the Abramson Cancer Center, and Director of Cancer Genetics for the Abramson Family Cancer Research Institute at the University of Pennsylvania. Additionally, heis on the scientific advisory board for the Harvard Nurses' Health Studies I and II.

Dr. Chodosh's research focuses on genetic, genomic and molecular approaches to understanding breast cancer susceptibility and pathogenesis.

Link:
Breast Cancer Research | Home page

Induced pluripotent stem cell Wikipedia StemCell Therapy

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[1] He was awarded the 2012 Nobel Prize along with Sir John Gurdon for the discovery that mature cells can be reprogrammed to become pluripotent. [2]

Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) [3] of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines.

Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease.[4]

iPSCs are typically derived by introducing products of specific set of pluripotency-associated genes, or reprogramming factors, into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the transcription factors Oct4 (Pou5f1), Sox2, cMyc, and Klf4. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.

iPSC derivation is typically a slow and inefficient process, taking 12 weeks for mouse cells and 34 weeks for human cells, with efficiencies around 0.01%0.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanakas team at Kyoto University, Japan, in 2006.[1] They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts. The fibroblasts were engineered so that any cells reactivating the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15.

Similar to ESCs, these iPSCs had unlimited self-renewal and were pluripotent, contributing to lineages from all three germ layers in the context of embryoid bodies, teratomas, and fetal chimeras. However, the molecular makeup of these cells, including gene expression and epigenetic marks, was somewhere between that of a fibroblast and an ESC, and the cells failed to produce viable chimeras when injected into developing embryos.

In June 2007, three separate research groups, including that of Yamanakas, a Harvard/University of California, Los Angeles collaboration, and a group at MIT, published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the gold standard for pluripotent stem cells.

These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs.[5][6][7][8]

Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered the original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanakas group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, OCT4, SOX2, KLF4, and C-MYC, using a retroviral system,[9] while Thomson and colleagues used a different set of factors, OCT4, SOX2, NANOG, and LIN28, using a lentiviral system.[10]

Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible.[11][12] In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck.[13][14] In 2010, iPSCs were derived from peripheral blood cells,[15][16] and in 2012, iPSCs were made from renal epithelial cells in the urine.[17]

Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure),[11][12] time it takes to expand the population of starting cells,[11] and the ability to differentiate into a given cell type.[18]

[citation needed]

The generation of iPS cells is crucially dependent on the transcription factors used for the induction.

Oct-3/4 and certain products of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table at right summarizes the key strategies and techniques used to develop iPS cells over the past half-decade. Rows of similar colors represents studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use small compounds that can mimic the effects of transcription factors. These molecule compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanakas traditional transcription factor method).[32] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[33] Deng et al. of Beijing University reported on July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[34][35]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the MET (mesenchymal-epithelial transition) process in which fibroblasts are pushed to a stem-cell like state, Dings group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, Thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks. [36][37]

In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[38] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

Another key strategy for avoiding problems such as tumor genesis and low throughput has been to use alternate forms of vectors: adenovirus, plasmids, and naked DNA and/or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[39] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[40] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[41] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the PiggyBac Transposon System. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis. [42]

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[43]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[44] On 4 June 2014, the lead author, Obokata agreed to retract both the papers [45] after she was found to have committed research misconduct as concluded in an investigation by RIKEN on 1 April 2014.[46]

MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential.[47] Addition of microRNAs can also be used to enhance iPS potential. Several mechanisms have been proposed.[47] ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance the efficiency of induced pluripotency by acting downstream of c-Myc.[48]microRNAs can also block expression of repressors of Yamanakas four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors.[47]

Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem (ES) cells, in many aspects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed.[49]

Gene expression and genome-wide H3K4me3 and H3K27me3 were found to be extremely similar between ES and iPS cells.[50][citation needed] The generated iPSCs were remarkably similar to naturally isolated pluripotent stem cells (such as mouse and human embryonic stem cells, mESCs and hESCs, respectively) in the following respects, thus confirming the identity, authenticity, and pluripotency of iPSCs to naturally isolated pluripotent stem cells:

Recent achievements and future tasks for safe iPSC-based cell therapy are collected in the review of Okano et al.[62]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells.[63] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound[64]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[65][66] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy patients, providing insight into the pathophysiology of the disease.[67] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of disease. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[68] Furthermore, combining hiPSC technology and genetically-encoded voltage and calcium indicators provided a large-scale and high-throughput platform for cardiovascular drug safety screening.[69]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human liver buds (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocytes (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the liver quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[70][71] Using this method, cells from one mouse could be used to test 1,000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.[72]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified vascular progenitor, the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[73][74]

Labelled iPSCs-derived NSCs injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed.[75]

Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there is still a critical need for blood for transfusion. In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016.[76]

The first human clinical trial using autologous iPSCs was approved by the Japan Ministry Health and was to be conducted in 2014 in Kobe. However the trial was suspended after Japans new regenerative medicine laws came into effect last November.[77] iPSCs derived from skin cells from six patients suffering from wet age-related macular degeneration were to be reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet would be transplanted into the affected retina where the degenerated RPE tissue was excised. Safety and vision restoration monitoring would last one to three years.[78][79] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and it eliminates the need to use embryonic stem cells.[79]

See the original post here: Induced pluripotent stem cell Wikipedia

This entry was posted on December 13, 2016 at 6:42 am and is filed under Arthritis. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |

See the article here:
Induced pluripotent stem cell Wikipedia StemCell Therapy

Induced stem cells – Wikiversity

Welcome to the Wikiversity learning project for Induced stem cells (Guide to publications). This project provides learning resources that help participants learn about Induced stem cells and efforts to produce useful stem cells and obtaining their derivatives for medical therapies. Participants should feel free to ask questions on discuss page and explore related topics.

Induced stem cells (iSC) are stem cells artificially derived from somatic, reproductive, pluripotent or other cell types by deliberate w:epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor (multipotentiMSC, also called an induced multipotent progenitor celliMPC) or unipotent -- (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

Three techniques are widely recognized:[1]

Back in 1895, Thomas Morgan remove one of the two frog w:blastomeres and found that w:amphibians are able to form whole w:embryo from the remaining part. This meant that the cells can change their differentiation pathway. Later, in 1924, Spemann and Mangold demonstrated the key importance of cellcell inductions during animal development.[20] The reversible transformation of cells of one differentiated cell type to another is called w:metaplasia.[21] This transition can be a part of the normal maturation process, or caused by an inducing stimulus. For example: transformation of iris cells to lens cells in the process of maturation and transformation of w:retinal pigment epithelium cells into the neural retina during regeneration in adult w:newt eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells. In w:Drosophila imaginal discs, cells have to choose from a limited number of standard discrete differentiation states. The fact that transdetermination (change of the path of differentiation) often occurs for a group of cells rather than single cells shows that it is induced rather than part of maturation.[22]

The researchers were able to identify the minimal conditions and factors that would be sufficient for starting the cascade of molecular and cellular processes to instruct pluripotent cells to organize the w:embryo. They show that opposing gradients of w:bone morphogenetic protein (BMP) and Nodal, two w:transforming growth factor family members that act as w:morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, w:in vivo or w:in vitro, uncommitted cells of the w:zebrafish w:blastula animal pole into a well-developed w:embryo.[23]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, differentiated airway epithelial cells can revert into stable and functional stem cells in vivo after the ablation of airway[24]. Another example, "chief" cells express the stem cell marker Troy. While they normally produce digestive fluids for the stomach, they can revert into stem cells to make temporary repairs to stomach injuries, such as a cut or damage from infection. Moreover, they can make this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, in essence serving as quiescent reserve stem cells.[25]

After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue[26] Macrophages can self-renew by local proliferation of mature differentiated cells.[27] In newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget the type of cell they had been. This capacity to regenerate does not decline with age and may be linked to their ability to make new stem cells from muscle cells on demand.[28]

A variety of nontumorigenic stem cells display the ability to generate multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant adult human stem cells that can self-renew. They form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency and can differentiate into w:endodermal, ectodermal and mesodermal cells both in vitro and in vivo.[29][30][31][32][33][34]

Other well-documented examples of w:transdifferentiation and their significance in development and regeneration were described in detail.[35]

Induced totipotent cells usually can be obtained by reprogramming somatic cells by w:somatic-cell nuclear transfer (SCNT) to the recipient eggs or oocytes.[3][5][36][37]

Using an approach based on the protocol outlined by Tachibana et al.,[3] hESCs can be generated by SCNT using dermal fibroblasts nuclei from both a middle-aged 35-year-old male and an elderly, 75-year-old male, suggesting that age-associated changes are not necessarily an impediment to SCNT-based nuclear reprogramming of human cells.[38] Such reprogramming of somatic cells to a pluripotent state holds huge potentials for w:regenerative medicine. Unfortunately, the cells generated by this technology, potentially are not completely protected from the immune system of the patient (donor of nuclei), because they have the same w:mitochondrial DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for w:autologous stem cell transplantation therapy, as for the present, it is not clear whether it can induce an immune response of the patient upon treatment.

Induced androgenetic haploid embryonic stem cells can be used instead of sperm for cloning. These cells, synchronized in M phase and injected into the oocyte can produce viable offspring.[39]

These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells,[40] offer the possibility of industrial production of transgenic farm animals.

Repeated recloning of viable mice through a SCNT method that includes a w:histone deacetylase inhibitor, trichostatin, added to the cell culture medium,[41] show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors[42]

Concerns still exist regarding telomere length resetting in cloned embryos and nuclear transfer ES cells, and possibilities of premature aging of cloned animals achieved by SCNT. It was shown that telomeres of cloned pigs generated by standard SCNT methods are not effectively restored, compared with those of donor cells, however trichostatin A significantly increases telomere lengths in cloned pigs and this could be one of the mechanisms underlying improved development of cloned embryos and animals treated with trichostatin.[43]

However, research into technologies to develop sperm and egg cells from stem cells raises bioethical issues.[44]

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes.[3][45] For example, the technology could prevent inherited w:mitochondrial disease from passing to future generations. Mitochondrial genetic material is passed from mother to child. Mutations can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and other neurological diseases. The nucleus from one human egg has been transferred to another, including its mitochondria, creating a cell that could be regarded as having two mothers. The eggs were then fertilised, and the resulting embryonic stem cells carried the swapped mitochondrial DNA.[46] As evidence that the technique is safe author of this method points to the existence of the healthy monkeys that are now more than four years old and are the product of mitochondrial transplants across different genetic backgrounds.[47]

In late-generation w:telomerase-deficient (Terc/) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming.[48]

Other cloning and totipotent transformation achievements have been described.[49]

Recently some researchers succeeded to get the totipotent cells without the aid of SCNT. Totipotent cells were obtained using the epigenetic factors such as oocyte germinal isoform of histone.[50] Reprogramming in vivo, by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice, confers totipotency features. Intraperitoneal injection of such in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic (w:trophectodermal) markers.[51]

iPSc were first obtained in the form of transplantable w:teratocarcinoma induced by grafts taken from mouse embryos.[52] Teratocarcinoma formed from somatic cells.[53]Genetically mosaic mice were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency.[54][55][56] It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent w:embryonic stem cell in an undifferentiated state, by supplying the culture medium with various factors.[57] In the 1980s, it became clear that transplanting pluripotent/embryonic stem cells into the body of adult mammals, usually leads to the formation of w:teratomas, which can then turn into a malignant tumor teratocarcinoma.[58] However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the w:inner cell mass and often produced a normal chimeric (i.e. composed of cells from different organisms) animal.[59][60][61] This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche").

In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic w:fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely w:Oct4, w:Sox2, w:Klf4 and w:c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes.[7]

Later has been found a reprogramming factor BRD3R that increases the efficiency of creating human induced pluripotent stem cells (HiPSCs) from skin fibroblasts in xeno-free media more than 20-fold, speeds the reprogramming time by several days and enhances the quality of reprogramming.[62] Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes.[63] IPSC properties are very similar to ESCs[64]. iPSCs have been shown to support the development of all-iPSC mice using a w:tetraploid (4n) embryo,[65] the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster.[18]

An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients.[9][66][67]

Reprogramming somatic cells to iPSC leads to rejuvenation. It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives.[68] Thus, reprogramming leads to the restoration of embryonic telomere length,[69] and hence increases the potential number of cell divisions otherwise limited by the w:Hayflick limit.[70]

However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an w:immune response,[71] which can be used for medical purposes,[72] or the formation of tumors such as teratoma.[73] The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic w:protein isoforms.[74] So, the immune system might detect and attack cells that are not cooperating properly.

A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis (via w:cytochrome c release across the w:mitochondrial outer membrane) in human pluripotent stem cells, but not in differentiated cells. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypothesized to be due to the changes undergone by pluripotent stem cell mitochondria in the process of cell differentiation. This ability of MitoBloCK-6 to separate the pluripotent and differentiated cell lines has the potential to reduce the risk of teratomas and other problems in regenerative medicine.[75]

In 2012 other w:small molecules (selective cytotoxic inhibitors of human pluripotent stem cellshPSCs) were identified that prevented human pluripotent stem cells from forming teratomas in mice. The most potent and selective compound of them (PluriSIn #1) inhibits stearoyl-coA desaturase (the key enzyme in w:oleic acid biosynthesis), which finally results in apoptosis. With the help of this molecule the undifferentiated cells can be selectively removed from culture.[76] An efficient strategy to selectively eliminate pluripotent cells with teratoma potential is targeting pluripotent stem cell-specific antiapoptotic factor(s) (i.e., w:survivin or Bcl10). A single treatment with chemical survivin inhibitors (e.g., w:quercetin or YM155) can induce selective and complete cell death of undifferentiated hPSCs and is claimed to be sufficient to prevent teratoma formation after transplantation.[77] However, it is unlikely that any kind of preliminary clearance,[78] is able to secure the replanting iPSC or ESC. After the selective removal of pluripotent cells, they re-emerge quickly by reverting differentiated cells into stem cells, which leads to tumors.[79] This may be due to the disorder of let-7 regulation of its target Nr6a1 (also known as w:Germ cell nuclear factor - GCNF), an embryonic transcriptional repressor of pluripotency genes that regulates gene expression in adult fibroblasts following w:micro-RNA miRNA loss.[80]

Yijie Geng et al., identified a small molecule, Displurigen, that potently disrupts pluripotency by targeting heat shock 70-kDa protein 8 (HSPA8), which maintains pluripotency by facilitating the DNA-binding activity of OCT4[81]

Teratoma formation by pluripotent stem cells may be caused by low activity of PTEN enzyme, reported to promote the survival of a small population (0,1-5% of total population) of highly tumorigenic, aggressive, teratoma-initiating embryonic-like carcinoma cells during differentiation. The survival of these teratoma-initiating cells is associated with failed repression of w:Nanog as well as a propensity for increased glucose and cholesterol metabolism.[82] These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells.[83] In connection with the above safety problems, the use iPSC for cell therapy is still limited.[84] However, they can be used for a variety of other purposes - including the modeling of disease,[85] screening (selective selection) of drugs, toxicity testing of various drugs.[86]

It is interesting to note that the tissue grown from iPSCs, placed in the "chimeric" embryos in the early stages of mouse development, practically do not cause an immune response (after the embryos have grown into adult mice) and are suitable for autologous transplantation[87] At the same time, full reprogramming of adult cells in vivo within tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs.[51] Furthermore, partial reprogramming of cells toward pluripotency in vivo in mice demonstrates that incomplete reprogramming entails epigenetic changes (failed repression of w:Polycomb targets and altered w:DNA methylation) in cells that drive cancer development.[88]

Several methods have been reported that may increase the safety and eventually the efficacy of iPSC-based regenerative medicine. The first safety approach eliminates potential oncogenic factors, such as the expression of oncogene c-myc, or integrates the reprogramming transgenes into chromosomes. The latter would be eliminated by using so-called nonintegrating viral vectors. The second safety approach is based on the isolation of desired differentiated cells from other cell types and undifferentiated human pluripotent stem cells (hPSCs), such as the removal of the residual pluripotent cells using fluoresecent activated cell sorting or magnetic beads coated with antibodies against a particular antigen, including SSEA-5 and Claudin-6, and fucose-specific lectin UEA (Ulex europaeus agglutinin)-I. The third safety approach entails the direct targeting and killing of oncogenic cells by using cytotoxic antibody recognizing podocalyxin-like protein-1, a chemical inhibitor of stearoyl-coA desaturase, specific monoclonal antibodies, DNA topoisomerase II inhibitor, and suicide gene therapy under transcriptional control of a pluripotency-related promoter[90][91]. However, these strategies may not suffice to lower risk to acceptable levels, because the tumorigenic risk of iPSC-based cell therapy arises not just from contamination with undifferentiated iPSCs but also from other unexpected events associated with long-term culture for reprogramming and redifferentiation. There is always a chance of unexpected issues associated with first-in-human clinical studies. An efficient and reliable approach to provide safety for future regenerative therapy and first-in-human cell therapy can be a suicide gene engineered from human caspase-9, that is not immunogenic, and can kill transduced cells in a cell-cycle-independent manner[92][93][94][95].

Miki Ando et al.[96] demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 system in vivo with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. They introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that rejCTLs from iPSCs are expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. Upon induction, the iC9 system efficiently leads to apoptosis in rejuvenated CTLs. This safeguard system can eliminate contaminating iPSCs, debulk tumors originated from iPSCs, stop cytokine release syndrome associated with iPSC-derived CTL therapy, and control on-target, off-tumor toxicities. It should be applicable to other cell therapies using iPSC-derived cells.

The potential to develop patient-derived cells into any cell type makes human pluripotent stem cells one of the most promising sources for regenerative treatments. The proper differentiation of autologous iPSCs sometimes results in a loss of immunogenicity and leads to the induction of tolerance.[97] This differentiation of iPSCs to mature cell typesand ultimately to functional tissues and organsholds great promise for personalized disease modeling, drug screening, and the development of cell-based therapies. [98] However there are some problems that need to be solved previously:

The main steps for the production of human pluripotent stem cell-derived progenitor cells under safe and good manufacturing practice (GMP) conditions must include:

The data collected throughout such process already have led to approval for a first-in-man clinical trial of transplantation of SSEA-1+ progenitors in patients with severely impaired cardiac function. [102].

Lonza attempted to develop clinically compliant processes to generate cGMP-compliant human iPSC lines and have described a step-by-step cGMP-compliant process to generate clinically compliant cell lines[103].

Several works have reported evidence of genomic instability in iPSC, raising concerns on their biomedical use. The reasons behind the genomic instability observed in iPSC remain mostly unknown. Sergio Ruiz et al.[104] show that, similar to the phenomenon of oncogene-induced replication stress, the expression of reprogramming factors induces replication stress. Increasing the levels of the checkpoint kinase 1 (CHK1) reduces reprogramming-induced replication stress and increases the efficiency of iPSC generation. Similarly, nucleoside supplementation during reprogramming reduces the load of DNA damage and genomic rearrangements on iPSC. So, lowering replication stress during reprogramming, genetically or chemically, provides a simple strategy to reduce genomic instability on mouse and human iPSC.

By using solely w:small molecules, Deng Hongkui and colleagues demonstrated that endogenous master genes are enough for cell fate reprogramming. They induced a pluripotent state in adult cells from mice using seven small-molecule compounds.[17] The effectiveness of the method is quite high: it was able to convert 0.2% of the adult tissue cells into iPSCs, which is comparable to the gene insertion conversion rate. The authors note that the mice generated from CiPSCs were "100% viable and apparently healthy for up to 6 months.So. This chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.[105]

iPS-like cells (iPSLCs) were also generated from mouse somatic cells in two steps with small molecule compounds. In the first step, stable intermediate cells were generated from mouse astrocytes by Shh activators (oxysterol and purmorphamine) to replace Bmi1 function. These cells called induced epiblast stem cell (EpiSC)-like cells (iEpiSCLCs) are similar to EpiSCs in terms of expression of specific markers, epigenetic state, and ability to differentiate into three germ layers. In the second step, treatment with MEK/ERK and GSK3 pathway inhibitors in the presence of leukemia inhibitory factor resulted in conversion of iEpiSCLCs into iPSLCs that were similar to mESCs, suggesting that Bmi1 is sufficient to reprogram astrocytes to partially reprogrammed pluripotency. So, combinations of small molecules can compensate for reprogramming factors and are sufficient to directly reprogram mouse somatic cells into iPSLCs. The chemically induced pluripotent stem cell-like cells (ciPSLCs) showed similar gene expression profiles, epigenetic status, and differentiation potentials to mESCs.[106]

The fact that human iPSCs capable of forming teratomas not only in humans but also in some animal body, in particular in mice or pigs, allowed to develop a method for differentiation of iPSCs in vivo. For this purpose, iPSCs with an agent for inducing differentiation into target cells are injected to genetically modified pig (such as biallelic RAG2 mutants[107]) or mouse that has suppressed immune system activation on human cells. The formed after a while teratoma is cut out and used for the isolation of the necessary differentiated human cells[108] by means of w:monoclonal antibody to tissue-specific markers on the surface of these cells. This method has been successfully used for the production of functional myeloid, erythroid, and lymphoid human cells suitable for transplantation (yet only to mice).[109] Mice engrafted with human iPSC teratoma-derived hematopoietic cells produced human B and T cells capable of functional immune responses. These results offer hope that in vivo generation of patient customized cells is feasible, providing materials that could be useful for transplantation, human antibody generation, and drug screening applications. Using MitoBloCK-6 [75] and / or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place even in the teratoma niche, offers hope that the resulting cells are sufficiently stable to stimuli able to cause their transition back to the dedifferentiated (pluripotent) state, and therefore safe. A similar in vivo differentiation system, yielding engraftable hematopoietic stem cells from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis, was described by Suzuki et al.[110] They noted that neither leukemia nor tumors were observed in recipients after intravenous injection of iPSC-derived hematopoietic stem cells into irradiated recipients. Moreover, this injection resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Such system provides a useful tool for practical application of iPSCs in the treatment of hematologic and immunologic diseases.[111]

For further development of this method animal in which is grown the human cell graft, for example mouse, must have so modified genome that all its cells express and have on its surface human SIRP.[112] To prevent rejection after transplantation to the patient of the allogenic organ or tissue, grown from the pluripotent stem cells in vivo in the animal, these cells should express two molecules: CTLA4-Ig, which disrupts T cell costimulatory pathways, and w:PD-L1, which activates T cell inhibitory pathway.[113]

Methods based on the detection of reporter gene-GFP-positive cells in the teratoma derived from iPSCs, will help to identify different types of induced adult stem cells which were previously difficult to pick out and to grow from selected cells tissue cultures.[114]

See also: US 20130058900 patent.

In the near-future, clinical trials designed to demonstrate the safety of the use of iPSCs for cell therapy of the people with age-related macular degeneration, a disease causing blindness through retina damaging, will begin. There are several articles describing methods for producing retinal cells from iPSCs[115][116] and how to use them for cell therapy.[117] Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation.[118] However, clinical trials have been successful: ten patients suffering from retinitis pigmentosa have had their eyesight restoredincluding a woman who had only 17 percent of her vision left. [119]

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or w:chronic obstructive pulmonary disease and w:asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal, and financial burden. So there is an urgent need for effective cell therapy and w:lung w:tissue engineering.[120][121] Several protocols have been developed for generation of the most cell types of the respiratory system, which may be useful for deriving patient-specific therapeutic cells.[122][123]

Some lines of iPSCs have the potentiality to differentiate into male germ cells and oocyte-like cells in an appropriate niche (by culturing in retinoic acid and porcine follicular fluid differentiation medium or seminiferous tubule transplantation). Moreover, iPSC transplantation make a contribution to repairing the testis of infertile mice, demonstrating the potentiality of gamete derivation from iPSCs in vivo and in vitro.[124]

Wu and his colleagues found that a combination of serum-free media plus fibroblast growth factor 2 (FGF2) and Wnt signaling inhibitors resulted in stable line of human rsPSCs (region-specific Induced stem cells)[125][126].

The transcriptomes of these cells resembled those of the posterior cells of the early mouse embryo, and grafting these cells into 7.5-day-old mouse embryos resulted in efficient incorporation in the posterior, but not the other parts of the embryo. After 36 hours of culturing these chimaeric embryos, the rsPSCs proliferated and could differentiate into the developing three germ layers, providing the first demonstration that human pluripotent cells can begin a differentiation program inside mice.

The region-specific cells could provide tremendous advantages -- the cells at this stage of an early embryo undergo dynamic changes to give rise to all cells, tissues and organs of the body. Each germ layer was theoretically capable of giving rise to specific tissues and organs. Whether human rsPSCs can generate more complicated tissue structures within mice or other animals requires further study[127].

These cells also have a lot of favorable characteristics for laboratory manipulation, including high cloning efficiency, stable passage in culture, and ease of genetic engineering.

The ease of culturing and editing the genome of human rsPSCs offers advantages for regenerative medicine applications.

The risk of cancer and tumors creates the need to develop methods for safer cell lines suitable for clinical use. An alternative approach is so-called "direct reprogramming" - transdifferentiation of cells without passing through the pluripotent state.[128][129][130][131][132][133] The basis for this approach was that 5-azacytidine - a DNA demethylation reagent - can cause the formation of w:myogenic, chondrogenic and adipogeni] clones in the immortal cell line of mouse embryonic fibroblasts[134] and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming.[135] Compared with iPSC whose reprogramming requires at least two weeks, the formation of induced progenitor cells sometimes occurs within a few days and the efficiency of reprogramming is usually many times higher. This reprogramming does not always require cell division.[136] The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas.[133]

Originally only early embryonic cells could be coaxed into changing their identity. Mature cells are resistant to changing their identity once they've committed to a specific kind. However, brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, specialized non-endodermal cells of the w:pharynx into fully differentiated intestinal cells in intact w:larvae and adult roundworm w:Caenorhabditis elegans with no requirement for a dedifferentiated intermediate.[137]

Determining the unique set of cellular factors that is needed to be manipulated for each cell conversion is a long and costly process that involved much trial and error. As a result, this first step of identifying the key set of cellular factors for cell conversion is the major obstacle researchers face in the field of cell reprogramming. An international collaboration of researchers from the Duke-NUS Medical School in Singapore, the University of Bristol in the United Kingdom, Monash University in Australia, and RIKEN in Japan have developed an algorithm, called Mogrify(1), that can predict the optimal set of cellular factors required to convert one human cell type to another. That will drastically reduce the time and effort needed to create induced stem cells When tested, Mogrify was able to accurately predict the set of cellular factors required for previously published cell conversions correctly. To further validate Mogrify's predictive ability, the team conducted two novel cell conversions in the laboratory using human cells, and these were successful in both attempts solely using the predictions of Mogrify.[138][139][140]

The future medical implications of this novel breakthrough in cellular reprogramming are not hard to imagine. A bewildering range of diseases and disorders could be relegated to the dustbin of medical historyfrom arthritis to macular degeneration, from lost limbs to cancer itself. Mogrify has been made available online for other researchers and scientists.

Another way of reprogramming is the simulation of the processes that occur during w:amphibian limb regeneration. In w:urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates into limb tissue. However, sequential small molecule treatment of the muscle fiber with myoseverin, w:reversine (the w:aurora B kinase inhibitor) and some other chemicals: BIO (glycogen synthase-3 kinase inhibitor), w:lysophosphatidic acid (pleiotropic activator of G-protein-coupled receptors), w:SB203580 (w:p38 MAP kinase inhibitor), or w:SQ22536 (adenylyl cyclase inhibitor) causes the formation of new muscle cell types as well as other cell types such as precursors to fat, bone and nervous system cells.[141]

The researchers discovered that GCSF-mimicking w:antibody can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells that normally develop into white blood cells to become neural progenitor cells. The technique[142] enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect.[143]

Schlegel and Liu[144] demonstrated that the combination of feeder cells[145][146][147] and a w:Rho kinase inhibitor (Y-27632) [148][149] induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal of Y-27632 and feeders allows the cells to differentiate normally.[144][150][151] CRC technology can generate 2106 cells in 5 to 6 days from needle biopsies and can generate cultures from cryopreserved tissue and from fewer than four viable cells. CRCs retain a normal w:karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors.[144][152][153]

The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking.[144][152][153] Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor.[154] In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host. While initial studies revealed that co-culturing epithelial cells with Swiss 3T3 cells J2 was essential for CRC induction, with transwell culture plates, physical contact between feeders and epithelial cells is not required for inducing CRCs, and more importantly that irradiation of the feeder cells is required for this induction. Consistent with the transwell experiments, conditioned medium induces and maintains CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells.[155]

A different approach to CRC is to inhibit w:CD47 - a w:membrane protein that is the w:thrombospondin-1 receptor. Loss of CD47 permits sustained proliferation of primary w:murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent w:embryoid body-like clusters. CD47 knockdown acutely increases w:mRNA levels of c-Myc and other stem cell transcription factors in cells in vitro and in vivo. Thrombospondin-1 is a key environmental signal that inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.[156] In vivo blockade of CD47 using an antisense w:morpholino increases survival of mice exposed to lethal total body irradiation due to increased proliferative capacity of bone marrow-derived cells and radioprotection of radiosensitive gastrointestinal tissues.[157]

Indirect lineage conversion is a reprogramming methodology in which somatic cells transition through a plastic intermediate state of partially reprogrammed cells (pre-iPSC), induced by brief exposure to reprogramming factors, followed by differentiation in a specially developed chemical environment (artificial niche).[158]

This method could be both more efficient and safer, since it does not seem to produce tumors or other undesirable genetic changes, and results in much greater yield than other methods. However, the safety of these cells remains questionable. Since lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, a fraction of the cells could acquire pluripotent properties if they do not stop the de-differentation process in vitro or due to further de-differentiation in vivo.[159]

A common feature of pluripotent stem cells is the specific nature of protein w:glycosylation of their outer membrane. That distinguishes them from most nonpluripotent cells, although not w:white blood cells.[160] The w:glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many w:stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA-3, SSEA-4, Tra 1-60, and Tra 1-81.[161] Suila Heli et al.[162] speculate that in human stem cells extracellular O-GlcNAc and extracellular O-LacNAc, play a crucial role in the fine tuning of w:Notch signaling pathway - a highly conserved cell signaling system, that regulates cell fate specification, differentiation, leftright asymmetry, apoptosis, somitogenesis, angiogenesis, and plays a key role in stem cell proliferation (reviewed by Perdigoto and Bardin[163] and Jafar-Nejad et al.[164])

Changes in outer membrane protein glycosylation are markers of cell states connected in some way with pluripotency and differentiation.[165] The glycosylation change is apparently not just the result of the initialization of gene expression, but perform as an important gene regulator involved in the acquisition and maintenance of the undifferentiated state.[166]

For example, activation of w:glycoprotein ACA,[167] linking glycosylphosphatidylinositol on the surface of the progenitor cells in human peripheral blood, induces increased expression of genes Wnt, w:Notch-1, w:BMI1 and w:HOXB4 through a signaling cascade w:PI3K/w:Akt/mTor/PTEN, and promotes the formation of a self-renewing population of hematopoietic stem cells.[168]

Furthermore, dedifferentiation of progenitor cells induced by ACA-dependent signaling pathway leads to ACA-induced pluripotent stem cells, capable of differentiating in vitro into cells of all three w:germ layers.[169] The study of w:lectins' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin w:Erythrina crista-galli (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells.[170]

w:Cell adhesion protein E-cadherin is indispensable for a robust pluripotent w:phenotype.[171] During reprogramming for iPS cell generation, N-cadherin can replace function of E-cadherin.[172] These functions of cadherins are not directly related to adhesion because sphere morphology helps maintaining the "stemness" of stem cells.[173] Moreover, sphere formation, due to forced growth of cells on a low attachment surface, sometimes induces reprogramming. For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors.

Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells epigenetic state. Specifically, "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)a subunit of H3 methyltranferaseby microgrooved surfaces lead to increased histone H3 acetylation and methylation". Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state.[174]

Substrate rigidity is an important biophysical cue influencing neural induction and subtype specification. For example, soft substrates promote neuroepithelial conversion while inhibiting w:neural crest differentiation of hESCs in a BMP4-dependent manner. Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive Smad w:phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and w:actomyosin w:cytoskeleton integrity and w:contractility.[175]

An initial sensing event of tissue and extracellular matrix (ECM) stiffness includes a pathway consisting of focal adhesion kinase (FAK), the adaptor protein p130Cas (Cas - Crk-associated substrates), and the guanosine triphosphatase Rac which selectively transduce ECM stiffness into stable intracellular stiffness, to increase the abundance of the cell cycle protein cyclin D1, and to promote S-phase entry. Rac-dependent intracellular stiffening involve its binding partner lamellipodin, a protein that transmits Rac signals to the cytoskeleton during cell migration. Such mechanotransduction by a FAK-Cas-Rac-lamellipodin signaling module converts the external information encoded by ECM stiffness into stable intracellular stiffness and mechanosensitive cell cycling.[176]

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the w:cytokine w:leukemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, accompanied by an increase in cellsubstratum w:adhesion and cell spreading. Restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biosubstrates, or by manipulating the w:cytoskeleton allowed the cells to remain in an undifferentiated and pluripotent state. The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or w:siRNA does not promote differentiation.[177] Possible mechanisms of stem cell fate predetermination by physical interactions with the extracellular matrix have been described.[178]

Cells involved in the reprogramming process change morphologically as the process proceeds. This results in physical difference in adhesive forces among cells. Substantial differences in 'adhesive signature' between pluripotent stem cells, partially reprogrammed cells, differentiated progeny and somatic cells allowed to develop separation process for isolation of pluripotent stem cells in w:microfluidic devices,[179][180] which is: fast (separation takes less than 10 minutes); efficient (separation results in a greater than 95 percent pure iPS cell culture); innocuous (cell survival rate is greater than 80 percent and the resulting cells retain normal transcriptional profiles, differentiation potential and karyotype).

Discussion on potential future applications of lab-on-a-chips for stem cell research, see in[181]

A novel method for cell reprogramming and fully automating stem cell cultures entire process is been developed by using smart surfaces that make cell adhesion and de-adhesion possible depending on changes in the environment.[182] This iterative method of cell culture enables to completely automate and remove the need for human involvement in the cell separation and washing stages, without using any additives that increase the toxicity level (such as trypsin).[183]

Stem cells possess mechanical memory (they remember past physical signals)with the w:Hippo signaling pathway factors:[184] Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) acting as an intracellular mechanical rheostatthat stores information from past physical environments and influences the cells fate.[185][186]

Stroke and many neurodegenerative disorders such as Parkinson's disease, Alzheimers disease, amyotrophic lateral sclerosis need cell replacement therapy. The successful use of converted neural cells (cNs) in transplantations open a new avenue to treat such diseases.[187] Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed and exhibit very limited proliferative ability that may not provide enough autologous donor cells for transplantation.[188] Self-renewing induced neural stem cells (iNSCs) provide additional advantages over iNs for both basic research and clinical applications.[131][132][133][189][190]

For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form iNSCs that self-renew in culture and after transplantation can survive and integrate without forming tumors in mouse brains.[191] INSCs can be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method for autologous transplantation or for the development of cell-based disease models.[190]

Neural chemicaly-induced progenitor cells (ciNPCs) can be generated from mouse tail-tip fibroblasts and human urinary somatic cells without introducing exogenous factors, but - by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, RepSox, an inhibitor of w:TGF beta signaling pathways), under a physiological hypoxic condition.[192] Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase, and TGF- pathways (where: w:sodium butyrate (NaB) or w:Trichostatin A (TSA) could replace VPA, w:Lithium chloride (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with w:SB-431542 or w:Tranilast) show similar efficacies for ciNPC induction.[192]

Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described.[193]

Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human w:astrocytes directly in the brain that are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl1, Brn2a and w:Myt1l) are activated after transplantation using a drug.[194]

w:Astrocytesthe most common w:neuroglial brain cells, which contribute to w:scar formation in response to injurycan be directly reprogrammed in vivo to become functional neurons that formed networks in mice without the need of cell transplantation.[195] The researchers followed the mice for nearly a year to look for signs of tumor formation and reported finding none. The same researchers have turned scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons in the injured adult spinal cord.[196]

Without w:myelin to insulate neurons, nerve signals quickly lose power. Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that cannot propagate to nerve endings, and as a consequence lead to cognitive, motor and sensory problems. Transplantation of w:oligodendrocyte precursor cells (OPCs), which can successfully create myelin sheaths around nerve cells, is a promising potential therapeutic response. Direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells provides a potential source of OPCs. Conversion by forced expression of both eight[197] or of the three[198] transcription factors Sox10, Olig2 and Zfp536, may provide such cells.

Cell-based in vivo therapies may provide a transformative approach to augment vascular and muscle growth and to prevent non-contractile scar formation by delivering transcription factors[128] or microRNAs[14] to the heart.[199] Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of cardiac core transcription factors ( GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1, Myocardin and ZFPM2) after coronary ligation.[128][200] These results implicated therapies that can directly remuscularize the heart without cell transplantation. However, the efficiency of such reprogramming turned out to be very low and the phenotype of received cardiomyocyte-like cells does not resemble those of a mature normal cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes.[201]

Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred.[202][203] Efficient cardiac differentiation of human iPS cells gave rise to progenitors that were retained within infarcted rat hearts, and reduced remodeling of the heart after ischemic damage.[204]

Furthermore, w:ischemic cardiomyopathy in the murine infarction model was targeted by iPS cell transplantation. It synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from w:decompensation by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling.[205] One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical w:Wnt signaling pathway at defined time points in during differentiation, using readily accessible small molecule compounds.[206]

Discovery of the mechanisms controlling the formation of cardiomyocytes led to the development of the drug ITD-1, which effectively clears the cell surface from TGF- receptor type II and selectively inhibits intracellular TGF- signaling. It thus selectively enhances the differentiation of uncommitted w:mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells.[207]

One project seeded decellularized mouse hearts with human iPSC-derived multipotential cardiovascular progenitor cells. The introduced cells migrated, proliferated and differentiated in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the hearts. In addition, the heart's extracellular matrix (the substrate of heart scaffold) signalled the human cells into becoming the specialised cells needed for proper heart function. After 20 days of perfusion with growth factors, the engineered heart tissues started to beat again and were responsive to drugs.[208]

See also: review[209]

w:Tbx18 transduction is a method of turning on genes in heart muscle cells as a treatment for certain w:cardiac arrhythmias. Tbx18 gene therapy is aimed at treating a group of arrhythmias known as sick sinus syndrome. In a healthy heart, w:sinoatrial node (SAN) cells act as the hearts pacemaker and cause the heart to beat in a regular rhythm. Approximately 10 thousand of the 10 billion cells in the heart are SAN cells.[210] The Tbx18 gene is required for development of pacemaker cells in the heart during fetal development but is normally not functional after birth[211] Tbx18 transduction converts atrial muscle cells into SAN cells that initiate the heartbeat. An engineered virus carrying the Tbx18 gene is injected into animals and infects atrial muscle cells. Inside atrial muscle cells the Tbx18 gene is expressed. Tbx18 turns on genes that drive SA node cell development, simultaneously turning off genes that create atrial muscle cells. Tbx18 gene therapy has been successful in rodent hearts, converting atrial muscle cells into SAN cells by expression of the Tbx18 transcription factor. Tbx18 expression in atrial myocytes was shown to convert them into functional SAN cells in an experiment done in rodents. These converted SAN cells are able to respond to the nervous system, allowing the heart to be regulated as normal. Adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.[212]

The elderly often suffer from progressive w:muscle weakness and regenerative failure owing in part to elevated activity of the p38 and p38 mitogen-activated kinase pathway in senescent skeletal muscle stem cells. Subjecting such stem cells to transient inhibition of p38 and p38 in conjunction with culture on soft w:hydrogel substrates rapidly expands and rejuvenates them that result in the return of their strength.[213]

In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of w:p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions.[214]

Myogenic progenitors for potential use in disease modeling or cell-based therapies targeting skeletal muscle could also be generated directly from induced pluripotent stem cells using free-floating spherical culture (EZ spheres) in a culture medium supplemented with high concentrations (100ng/ml) of fibroblast growth factor-2 (w:FGF-2) and w:epidermal growth factor.[215]

Unlike current protocols for deriving w:hepatocytes from human fibroblasts, Saiyong Zhu et al., (2014)[216] did not generate iPSCs but, using small molecules, cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) were efficiently differentiated. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of human primary adult hepatocytes. iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state. Acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level.[217]

These results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

Complications of Diabetes mellitus such as w:cardiovascular diseases, retinopathy, neuropathy, nephropathy, and peripheral circulatory diseases depend on sugar dysregulation due to lack of w:insulin from pancreatic w:beta cells and can be lethal if they are not treated. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs).[218] Unfortunately, human PSC-derived insulin-expressing cells resemble human fetal cells rather than adult cells. In contrast to adult cells, fetal cells seem functionally immature, as indicated by increased basal w:glucose secretion and lack of glucose stimulation and confirmed by w:RNA-seq of whose transcripts.[219]

Overexpression of the three transcription factors, w:PDX1 (required for pancreatic bud outgrowth and beta-cell maturation), NGN3 (required for endocrine precursor cell formation) and MAFA (for beta-cell maturation) combination (called PNM) can lead to the transformation of some cell types into a beta cell-like state.[220] An accessible and abundant source of functional insulin-producing cells is intestine. PMN expression in human intestinal w:organoids stimulates the conversion of intestinal epithelial cells into -like cells possibly acceptable for transplantation.[221]

Adult proximal tubule cells were directly transcriptionally reprogrammed to w:nephron progenitors of the embryonic w:kidney, using a pool of six genes of instructive transcription factors (SIX1, SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail homolog 2 (SNAI2)) that activated genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule cell line.[222] The generation of such cells may lead to cellular therapies for adult w:renal disease. Embryonic kidney organoids placed into adult rat kidneys can undergo onward development and vascular development.[223]

As blood vessels age, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including myocardial infarction, ischemic stroke and atherosclerosis of arteries supplying the heart, brain and lower extremities. So, an important goal is to stimulate vascular growth for the w:collateral circulation to prevent the exacerbation of these diseases. Induced Vascular Progenitor Cells (iVPCs) are useful for cell-based therapy designed to stimulate coronary collateral growth. They were generated by partially reprogramming endothelial cells.[158] The vascular commitment of iVPCs is related to the epigenetic memory of endothelial cells, which engenders them as cellular components of growing blood vessels. That is why, when iVPCs were implanted into w:myocardium, they engrafted in blood vessels and increased coronary collateral flow better than iPSCs, mesenchymal stem cells, or native endothelial cells.[224]

Ex vivo genetic modification can be an effective strategy to enhance stem cell function. For example, cellular therapy employing genetic modification with Pim-1 kinase (a downstream effector of w:Akt, which positively regulates neovasculogenesis) of w:bone marrowderived cells[225] or human cardiac progenitor cells, isolated from failing myocardium[226] results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance.

Read more from the original source:
Induced stem cells - Wikiversity