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Stem Cells in Culture Have Tendency to Develop Cancer-Linked Mutations – Genetic Engineering & Biotechnology News

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Stem cells that are grown in the lab are known to acquire mutations, but whether these mutations are particularly numerous or risky remains unclear. Mutations acquired in stem cell culture, it is feared, would complicate efforts to deploy stem cells in regenerative medicine. At the least, lab-grown stem cells may need to be screened for deleterious mutations, with special attention devoted to vulnerable portions of the genome or flaws that could lead to dire consequences, such as cancer.

To characterize the mutations that may arise among stem cells in vitro, scientists have been introducing gene-sequencing tests. For example, in a recent study, scientists based at Harvard have determined that human pluripotent stem cells are prone to develop mutations in the TP53 gene, which ordinarily helps suppress cancer. The mutated versions of the TP53 found by the Harvard team, however, tend to drive cancer development.

Details of this work appeared April 26 in the journal Nature, in an article entitled, Human Pluripotent Stem Cells Recurrently Acquire and Expand Dominant Negative P53 Mutations. This article describes how the Harvard team sequenced the protein-coding genes of 140 human embryonic stem cell (hES) cell lines26 of which were developed for therapeutic purposes using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 human pluripotent stem cell lines were listed on the NIH registry of human pluripotent stem cells. This gene-sequencing exercise was followed by computational work that allowed the scientists to identify mutations present in a subset of cells in each cell line.

[We] identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53, wrote the articles authors. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage.

The scientists also mined published RNA sequencing data from 117 human pluripotent stem cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the authors of the Nature paper detailed, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus.

These findings suggest that cell lines should be screened for mutations at various stages of development as well as immediately before transplantation.

"Our results underscore the need for the field of regenerative medicine to proceed with care," said the study's co-corresponding author Kevin Eggan, Ph.D. "[They] indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies. Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods."

"Cells in the lab, like cells in the body, acquire mutations all the time," added Steve McCarroll, Ph.D., co-corresponding author. "Mutations in most genes have little impact on the larger tissue or cell line. But cells with a pro-growth mutation can outcompete other cells, become very numerous, and 'take over' a tissue. We found that this process of clonal selectionthe basis of cancer formation in the bodyis also routinely happening in laboratories."

Although the Harvard scientists expected to find some mutations in stem cell lines, they were surprised to find that about 5% of the stem cell lines they analyzed had acquired mutations the TP53 gene, which encodes the tumor suppressor protein P53.

Nicknamed the "guardian of the genome," P53 controls cell growth and cell death. People who inherit p53 mutations develop a rare disorder called Li-Fraumeni Syndrome, which confers a near 100% risk of developing cancer in a wide range of tissue types.

The specific mutations that the researchers observed are "dominant negative" mutations, meaning, when present on even one copy of P53, they are able to compromise the function of the normal protein, whose components are made from both gene copies. The exact same dominant negative mutations are among the most commonly observed mutations in human cancers.

The researchers performed a sophisticated set of DNA analyses to rule out the possibility that these mutations had been inherited rather than acquired as the cells grew in the lab. In subsequent experiments, the Harvard scientists found that P53 mutant cells outperformed and outcompeted nonmutant cells in the lab dish. In other words, a culture with a million healthy cells and one P53 mutant cell, said Dr. Eggan, could quickly become a culture of only mutant cells.

"The spectrum of tissues at risk for transformation when harboring a P53 mutation include many of those that we would like to target for repair with regenerative medicine using human pluripotent stem cells," noted Dr. Eggan. Those organs include the pancreas, brain, blood, bone, skin, liver, and lungs.

However, Drs. Eggan and McCarroll emphasized that now that this phenomenon has been found, inexpensive gene-sequencing tests will allow researchers to identify and remove from the production line cell cultures with concerning mutations that might prove dangerous after transplantation.

The researchers point out in their paper that screening approaches to identify these P53 mutations and others that confer cancer risk already exist and are used in cancer diagnostics. In fact, in an ongoing clinical trial that is transplanting cells derived from induced pluripotent stem cells, or iPSCs, gene sequencing is used to ensure the transplanted cell products are free of dangerous mutations.

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Stem Cells in Culture Have Tendency to Develop Cancer-Linked Mutations - Genetic Engineering & Biotechnology News

Stem cell therapy relieves pain, restores joints – The Herald-News

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The 360+ joints in the human body link bones and keep our bodies flexible. Until they become painful. Physical discomfort, where bones meet to form a joint, can be mild to intensely agonizing when the joints cartilage, ligaments, tendons, or muscles become inflamed and sore. Pain in one joint may be the result of an injury, or a condition such as tendonitis. Pain in multiple joints may indicate arthritis or gout.

Many joint pain problems in the knees, hips, and shoulders can be relieved with stem cell injection therapy, according to Dr. Frank Ostir, Director, Ostir Physical Medicine in Joliet. He explains that stem cells have anti-inflammatory properties plus growth factors. They relieve pain and rebuild damaged joints by regenerating into new tissue and cartilage. Stem cells can also heal torn ligaments.

They speed up the bodys own healing abilities. Theres no risk of tissue rejection, and no toxic substances or side effects. This regenerative treatment gives the best results in the shortest amount of time, Ostir says.

This phenomenal advancement in regenerative medicine makes it possible for patients to be pain-free and possibly avoid surgery through a minimally invasive procedure performed in the office. The actual procedure takes about 15 minutes. We used guided imaging from fluoroscopy and ultrasound technology to inject the stem cells to the exact site of affliction. The stem cells are mixed with a local anesthetic and injected through a small needle, to minimize any discomfort.

Ostir continues, The patient usually rests on the day of the injection, and resumes regular activity afterwards. About 80 percent of healing occurs in the first two months of treatment, due to the rate of stem cells replicating. Its our hope that this truly amazing therapy will eliminate the need for drugs and surgery.

For more information, contact Ostir Physical Medicine, (815) 729-2022, or visit http://www.ostirphysicalmed.com.

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Stem cell therapy relieves pain, restores joints - The Herald-News

Combination therapy could provide new treatment option for ovarian cancer – Medical Xpress

By Stem Cell Treatment

May 1, 2017 Ovarian cancer tumors with higher percentages of cIAP-expressing cells, shown in red at left, were more sensitive to a potential combination therapy than tumor cells without cIAP-expressing cells. Credit: UCLA Broad Stem Cell Research Center

Researchers have been trying to understand why up to 85 percent of women experience recurrence of high-grade serous ovarian cancerthe most common subtype of ovarian cancerafter standard treatment with the chemotherapy drug carboplatin.

Preclinical research from Dr. Sanaz Memarzadeh, who is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has potentially solved this mystery and pinpointed a combination therapy that may be effective for up to 50 percent of women with ovarian cancer.

Memarzadeh's research, published in the journal Precision Oncology, shows a new combination therapy of carboplatin and an experimental drug called birinapant can improve survival in mice with ovarian cancer tumors. Additional findings reveal that testing for a specific protein could identify ovarian tumors for which the treatment could be effective. Importantly, the treatment could also target cancers that affect other parts of the body, including the bladder, cervix, colon and lung cancer.

In 2015, Memarzadeh and her team uncovered and isolated carboplatin-resistant ovarian cancer stem cells. These cells have high levels of proteins called cIAPs, which prevent cell death after chemotherapy. Since the cancer stem cells survive carboplatin treatment, they regenerate the tumor; with each recurrence of ovarian cancer, treatment options become more limited. Memarzadeh showed that birinapant, which degrades cIAPs, can make carboplatin more effective against some ovarian cancer tumors.

"I've been treating women with ovarian cancer for about two decades and have seen firsthand that ovarian cancer treatment options are not always as effective as they should be," said Memarzadeh, director of the G.O. Discovery Lab and member of the UCLA Jonsson Comprehensive Cancer Center. "Our previous research was promising, but we still had questions about what percentage of tumors could be targeted with the birinapant and carboplatin combination therapy, and whether this combination could improve overall survival by eradicating chemotherapy-resistant ovarian cancer tumors."

In this new study, the research team first tested whether the combination therapy could improve survival in mice. Half of the mice tested had carboplatin-resistant human ovarian cancer tumors and the other half had carboplatin-sensitive tumors. The team administered birinapant or carboplatin as well as the two drugs combined and then monitored the mice over time. While birinapant or carboplatin alone had minimal effect, the combination therapy doubled overall survival in half of the mice regardless of whether they had carboplatin-resistant or carboplatin-sensitive tumors.

"Our results suggest that the treatment is applicable in some, but not all, tumors," said Rachel Fujikawa, a fourth year undergraduate student in Memarzadeh's lab and co-first author of the study.

To assess the combination therapy's rate of effectiveness in tumors, the team went on to test 23 high-grade serous ovarian cancer tumors from independent patients. Some were from patients who had never been treated with carboplatin and some were from patients who had carboplatin-resistant cancer.

With these samples, the researchers generated ovarian cancer tumors utilizing a method called disease-in-a-dish modeling and tested the same treatments previously tested in mice. Once again, carboplatin or birinapant alone had some effect, while the combination of birinapant and carboplatin successfully eliminated the ovarian cancer tumors in approximately 50 percent of samples. Importantly, the combination therapy worked for both carboplatin-resistant and carboplatin-sensitive tumors.

The researchers also measured cIAPs (the target for the drug birinapant) in the tumors. They found a strong correlation between cancer stem cells with high levels of cIAP and a positive response to the combination therapy. Since elevated levels of cIAPs have been linked to chemotherapy resistance in other cancers, the researchers wondered if the combination therapy could effectively target those cancers as well.

The team created disease-in-a-dish models using human bladder, cervix, colon and lung cancer cells and tested the combination therapy. Similar to the ovarian cancer findings, 50 percent of the tumors were effectively targeted and high cIAP levels correlated with a positive response to the combination therapy.

"I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy," said Memarzadeh, gynecologic oncology surgeon and professor at the David Geffen School of Medicine at UCLA.

Explore further: Combination therapy may be more effective against the most common ovarian cancer

More information: V. La et al, Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy, npj Precision Oncology (2017). DOI: 10.1038/s41698-017-0008-z

High-grade serous ovarian cancer often responds well to the chemotherapy drug carboplatin, but why it so frequently comes back after treatment has been a medical mystery.

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Combination therapy could provide new treatment option for ovarian cancer - Medical Xpress

Stem Cells 101, the Value Proposition – Live Trading News

By Stem Cell Treatment

Stem Cells 101, the Value Proposition

The Key purpose of stem cells is to maintain, heal and regenerate tissues wherever they reside in our body. This is a continuous process that occurs inside the human body throughout its life.

If we did not have stem cells, our lifespan would be about 1 hour, because there would be nothing to replace exhausted cells or damaged tissue. In addition, any time the body is exposed to any sort of toxin, the inflammatory process causes stem cells to swarm the area to repair the damage.

As an example: Say you went to the gym in the morning and did some squats. As a result of that, you would get tiny tears inside the muscle. The stem cells that reside beneath the muscle would come out and repair those little tears.

The reason that, if you continuously go to the gym, you would start to build new muscle, is because those stem cells, hard at work underneath your muscle, are helping to repair and build that new muscle. This would apply to all of the tissues inside your body.

Sure, it is easy to think of stem cell therapy as a magic bullet,but is wise to implement strategies that nourish and thereby help optimize the stem cells we already have in our body.

As noted by Kristin Comella, named # 1 on the Academy of Regenerative Practices list of Top 10 stem cell innovators, has been a stem cell researcher for nearly 20 years: You have to create an appropriate environment for these cells to function in. If you are putting garbage into your body and you are constantly burdening your body with toxins, your stem cells are getting too distracted trying to fight off those toxins.

By creating an appropriate environment, optimizing your diet and reducing exposure to toxins, that will allow the stem cells that were putting in to really home in and focus on the true issue that were trying to treat.

The other thing weve discovered over the years is that [stem cell therapy] is not the type of thing where you take one dose and youre cured forever. Our tissues are constantly getting damaged Youre going to have to repeat-dose and use those stem cells to your advantage.

When you think about a lizard that loses its tail, it takes two years to grow back the tail. Why would we put unrealistic expectations on the stem cells that were trying to apply to repair or replace damaged tissue? This is a very slow process. This is something that will occur over months and may require repeat dosing.

In the past, stem cells were isolated from bone marrow, and were used for bone marrow transplants for cancer patients since the 1930s. But, stem cells come from just about any tissue in the human body, as every tissue contains stem cells.

Human bone marrow has very low amounts of mesenchymal stem cells now believed to be the most important, from a therapeutic perspective.

Mesenchymal stem cells help trigger an immunomodulatory response or a paracrine effect, which means they send signals out to the rest of your body, calling cells to the area to help promote healing.

What researchers have discovered recently is that a more plentiful source of stem cells is actually your fat tissue. Body fat can contain up to 500X more cells than bone marrow, as far as these mesenchymal type stem cells go.

One thing that is also critically important when youre talking about isolating the cells is the number of other cells that are going to be part of that population.

When youre isolating a bone marrow sample, this actually is very high in white blood cells, which are pro-inflammatory.

White blood cells are part of your immune response. When an injury occurs, or a foreign body enters your system, white blood cells will attack. Unfortunately, white blood cells do not discriminate, and can create quite a bit of damage as they clean the area out, Ms. Comella says.

Stem cells, in particular the mesenchymal cells, quiet down the white blood cells and then start the regeneration phase, which leads to new tissue.

Bone marrow tends to be very high in white blood cells and low in the mesenchymal cells. Isolating stem cells from fat tissue is preferred not only because its easier on the patient, but fat also contains a higher population of mesenchymal cells and fewer white blood cells.

The benefit also of isolating [stem cells from] fat is that its a relatively simple procedure. Theres typically no shortage of fat tissue, especially in Americans.

Also, as you age, your bone marrow declines with regards to the number of cells in it, whereas the fat tissue maintains a pretty high number of stem cells, even in older individuals.

We can successfully harvest fat off of just about anyone, regardless of their age or how thin they are. The procedure is done under local [anesthesia], meaning that the patient stays awake. They dont have to go under general anesthesia. We can harvest as few as 15 cubic centimeters of fat, which is a very small amount of fat, and still get a very high number of stem cells, Ms. Comella says.

A stem cell procedure can cost anywhere from $5,000 to $15,000, depending on what is being done, and rarely if ever will insurance cover it.

Still, when compared it to the cost of long-term medications or the out-of-pocket cost of getting a knee replacement, stem cell therapy may still be a less expensive alternative.

Also, a single extraction will typically yield enough stem cells for 20 to 25 future treatments, should one decide to store stem cells for future needs.

I think it is accessible for patients, Ms. Comella says. Its an out-patient procedure. One should plan to be in clinic for about 2 hours; no real limitations afterwards, just no submerging in water, no alcohol, no smoking for a week. But other than that, patients can resume their normal activities and go about their regular daily lives.

Interestingly, Ms. Comella notes that patients who eat a very healthy diet, focusing on Organic and grass fed meat, have body fat that is very hearty and almost sticky, yielding high amounts of very healthy stem cells.

We can grow much better and faster stem cells from that fat than [the fat from] somebody who eats a grain-based diet or is exposed to a lot of toxins in their diet, she says. Their fat tends to be very fluffy, buttery yellow. The cells that come out of that are not necessarily as good a quality. Its just been very interesting. And of note, patients that are cigarette smokers, their fat is actually gray-tinged in color. The stem cells do not grow well at all.

The beauty of stem cell therapy is that it mimics a process that is ongoing in the human body all the time. Our stem cells are continuously promoting healing, and they do not have to be manipulated in any way. The stem cells naturally know how to hone in on areas of inflammation and how to repair damaged tissue.

All we are doing is harnessing the cells from one location where theyre sitting dormant and relocating them to exactly where we want them and we need them to work, Ms.Comella says. Basically, anything inside your body that is inflamed, that is damaged in some way, that is lacking blood supply, the [stem] cells can successfully treat.

That means orthopedics, knee injections, shoulder injections, osteoarthritis, acute injuries, anterior cruciate ligament tears in your back back pain associated with degenerative disc disease or damaged tendons or ligaments, herniated and bulging discs. You can also use it in systemic issues, everything from diabetes, to cardiac, to lungs any tissue organ inside your body thats been damaged.

Autoimmune diseases [can also be treated]. The stem cells are naturally immunosuppressant, meaning they can help quiet down an over reactive immune system and help the immune system function in a more normal way. Neurological diseases, traumatic brain injury, amyotrophic lateral sclerosis, Parkinsons. All of these have to do with tissue thats not functioning properly. The cells can be used to address that.

The list of different diseases that could benefit from this intervention is very impressive.

And one can dramatically improve the benefits of stem cell intervention by combining it with other healthy lifestyle factors that optimize mitochondrial function, such as eating a healthy Real Food diet, exercising, sleeping well, avoiding toxins and detoxifying from toxic influences.

Stem cells can be used as part of an anti-aging program. Ms. Comella has used stem cells on herself for several years, and report feeling better now than she did a decade ago.

The ability to reduce inflammation inside your body is basically making yourself live longer. Inflammation is what kills us all. Its what makes our telomeres shrink. Its what causes us pain and discomfort. Its what makes the tissues start to die. The ability to dose yourself with stem cells and bring down your inflammation, which is most likely caused by any sort of toxin that youve been exposed to breathing air is exposure to toxins this is going to lengthen your lifespan.

I typically will do a dose every 6 to 12 months, regardless of whats going on. If I have anything thats bothering me, if I tweak my knee at the gym, then I absolutely will come in and do an injection in my knee. I want to keep my tissue healthy for as long as possible.

I want to stay strong. I dont want to wait until something is wrong with me. I think that this is the future of medicine. This is what were going to start to see. People will begin to get their regular doses of [their own] stem cells and itll just be common practice.

Keep in mind there is a gradual and progressive decline in the quality and the number of stem cells as we age, so when considering this approach, it would be prudent and advantageous to extract and bank stem cells as early on as possible. There are stem cell banking services available.

Your stem cells are never as young as they are right now. Every minute that you live, your telomeres are shrinking. The ability to lock in the youth of your cells today can be very beneficial for you going forward, and for your health going forward. God forbid something happens. What if you have a heart attack? Youre not going to get clearance to get a mini-lipo aspirate procedure.

If you have your cells waiting in the bank, ready for you, it becomes very easy to pull a dose and do an IV delivery of cells. Its almost criminal that were not doing this for every single one of our cardiac patients. This should be standard practice. We should be having every single patient bank their stem cells at a young age and have them waiting, ready and available. The technology is there. We have it. Im not sure why this technology is not being made available to everyone,says.

I think stem cell therapy is very different than traditional medicine. Stem cell therapy may actually make it so that you dont have to be dependent on pharmaceutical medications. You can actually repair the tissue and thats it. This is a very different way of viewing medicine,Ms. Comella says.

The amniotic products available in the US are not so much stem cell products as they are growth factor products.

According to Ms. Comella, they can be useful in creating an immunomodulatory response, which can help to promote healing, but that differs from the living stem cell procedures that can be done by either isolating cells from body fat or bone marrow. As a general rule, clinical benefits are not achieved when using an amniotic product, primarily because they do not contain living stem cells.

I want to contrast that to what are called embryonic stem cells, Ms.Comella adds. The products obtained from cord blood, from women who are having babies, are not embryonic stem cells. Embryonic stem cells are when you are first bringing the egg and sperm together. Three days after that, you can isolate what is called an inner cell mass. This inner cell mass can be used to then grow cells in culture, or that inner cell mass could eventually lead to the formation of a baby.

Those are embryonic stem cells, and those are pluripotential, meaning that they have the ability to form an entire being, versus adult stem cells or stem cells that are present in amniotic tissue, [which] are multipotential, which only have the ability to form subsets of tissue.

When dealing with different diseases or damaged tissue or inflammation, mostly you want to repair tissue. If somebody has damage in their knee, they do nnot necessarily need embryonic cells because they do not need a baby in their knee. They need new cartilage in their knee.

Stem cell therapy is very different than traditional medicine. Stem cell therapy may actually make it so that we do have to depend on pharmaceutical medications. And we can actually repair the tissue and be done with it. This is a very different way of viewing medicine.

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Paul A. Ebeling, polymath, excels in diverse fields of knowledge. Pattern Recognition Analyst in Equities, Commodities and Foreign Exchange and author of The Red Roadmasters Technical Report on the US Major Market Indices, a highly regarded, weekly financial market letter, he is also a philosopher, issuing insights on a wide range of subjects to a following of over 250,000 cohorts. An international audience of opinion makers, business leaders, and global organizations recognizes Ebeling as an expert.

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Stem Cells 101, the Value Proposition - Live Trading News

The Anabolic Era of Orthopaedics: Stem Cells which ones to use? – Huffington Post

By Stem Cell Clinic

Orthopaedic Tissues transplanted into humans are dead.

Thats right: Other than hearts, livers and kidneys for that must be kept alive for immediate transplantation, any tissue that is removed from a donor or a cadaver, frozen, washed, sterilized and finally delivered to a surgeon is dead. From there it may be used in new ACL grafts, meniscus replacements, rotator cuff patches, tendons for the hands and feet the list goes on.

The surgeon relies on the patients healing ability to recognize and revive the dead donor graft. The body does this by sending scavenger cells that open up pores for the new blood vessels to bore into, lacing new blood vessels into the tissue, and finally sending specialized cells that lay down new collagen and restore the graft to life. In ligaments, this wonderful tissue regeneration process is called ligamentization; in other tissues, remodeling.

But the process of remodeling takes time, and during that period of restoration the tissue is at its weakest stage. A new injury doesnt need to be very forceful to tear the healing tissue. And any illness might slow down the process. An early return to sports might put too much stress on the graft, leading to stretchingor, in the worst case, a complete failure to remodel.

But why, in the 21st century, do we rely on nature alone to heal our repaired and replaced tissues? Fortunately, the entire field of tissue regeneration is changing rapidlyand the Stone Research Foundation is at the forefront of this research.

We are now in what I call the Anabolic Era of orthopedics, where we add stem cells, growth factors, electrical stimulation and other factors to juice up the healing process. But stem cell science is advancing so rapidly that we now have off-the-shelf products with the highest desirable concentrations of stem cells and growth factors for every application.

Stem cells are pluripotent cells that produce a wide range of healing growth factors, along with anti-inflammatory, anti-scarring, and antimicrobial agents. A 50-year-old person has 1/4 the stem cells of a teenager.

Over the last few years, in the Stone Clinic, we concentrated and combined patients own stem cells and growth factors with donor tissues before using them to rebuild ACLs and meniscus tissue. This year, we have off-the-shelf amniotic tissue with validated live cells and 2 to 50 times the growth factor concentrations that we can obtain from the patients own blood. These tissues also contain millions of cellsmany times more than the few found in older peoples bone and fat. These off-the-shelf cells are immunoprivileged, meaning they are not rejected (for the same reason a mother does not reject the baby she carries) and do not form tumors.

Here is a short table of the stem cell sources today:

Pros: very vascular with many cells

Cons: Requires a surgical procedure; cell numbers decline with age.

Pros: Marrow cells are more similar to cartilage and bone

Cons: Painful bone marrow biopsy procedure; cell numbers decline with age

Pros: easy access with a needle puncture. Less expensive. Growth factors 2-5x normal

Cons: Very few stem cells.

Amniotic Fluid and Membranes:

Pros: 2-50x growth factor concentration. Very high concentration of stem cells. No second surgery.

Cons: Cost. Many preparations have dead cells. Quality control essential. If irradiated then low activity of growth factors.

Today, tissues transplanted in our clinic are pre-loaded with these amniotic growth factors and stem cells. We must now do the basic science to determine the optimal concentrations of these factors when infused into tissues and the clinical science to demonstrate if, and how much faster, the body heals with the use of these tissues.and if effective enough the application of stem cells and growth factors may quickly become widespread, leading to accelerated tissue repair.

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The Anabolic Era of Orthopaedics: Stem Cells which ones to use? - Huffington Post

Endothelial progenitor cell – Wikipedia

By Uncategorized

Endothelial progenitor cell (or EPC) is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endothelial cell formation.[1] Despite the history and controversy, the EPC in all its forms remains a promising target of regenerative medicine research.

Developmentally, the endothelium arises in close contact with the hematopoietic system. This, and the existence of hemogenic endothelium, led to a belief and search for adult hemangioblast- or angioblast-like cells; cells which could give rise to functional vasculature in adults.[2] The existence of endothelial progenitor cells has been posited since the mid-twentieth century, however their existence was not confirmed until the 1990s when Asahara et al. published the discovery of the first putative EPC.[3]

Recently, controversy has developed over the definition of true endothelial progenitors.[4] Although bone marrow-derived cells do appear to localize to injured vessels and promote an angiogenic switch, other studies have suggested these cells do not contribute directly to the functional endothelium, instead acting via paracrine methods to provide support for the resident endothelial cells.[5][6] While some other authors have contested these, and maintained that they are true EPCs,[7] many investigators have begun to term these cells colony forming unit-Hill cells (CFU-Hill) or circulating angiogenic cells (CAC) instead (depending on the method of isolation), highlighting their role as hematopoietic myeloid cells involved in promoting new vessel growth.[8][9]

Molecular genetic analysis of early outgrowth putative EPC populations suggests they do indeed have monocyte-like expression patterns, and support the existence of a separate population of progenitors, the late outgrowth, or endothelial colony forming cell (ECFC).[10] Furthermore, early outgrowth cells maintain other monocyte functions such as high Dil-Ac-LDL and India ink uptake and low eNOS expression. These original, early outgrowth, CFU-Hill or CACs are also shown to express CD14, a lipopolysaccharide receptor expressed by monocytes but not endothelial cells.[11]

Endothelial colony forming cells represent a distinct population that has been found to have the potential to differentiate and promote vessel repair. ECFCs are now known to be tissue-resident progenitor cells in adults that maintain some vasculogenic ability.[12]

By method of isolation and cell function, three main populations of putative adult EPCs have been described. The behavior of the cells can be found in the following table.[9][13]

EPCs also have variable phenotypic markers used for identification. Unfortunately, there are no unique markers for endothelial progenitors that are not shared with other endothelial or hematopoietic cells, which has contributed to the historical controversy surrounding the field. A detailed overview of current markers can be found in the following table.[2][13]

As originally isolated by Asahara et al., the CFU-Hill population is an early outgrowth, formed by plating peripheral blood mononuclear cells on fibronectin-coated dishes, allowing adhesion and depleting non-adherent cells, and isolating discrete colonies.[8][9]

A similar method is to culture the peripheral blood mononuclear fraction in supplemented endothelial growth medium, removing the non-adherent cells, and isolating the remaining. While these cells display some endothelial characteristics, they do not form colonies.[8][9]

Endothelial colony forming cells are a late outgrowth cell type; that is, they are only isolated after significantly longer culture than CFU-Hill cells. ECFCs are isolated by plating peripheral blood mononuclear fraction on collagen-coated plates, removing non-adherent cells, and culturing for weeks until the emergence of colonies with a distinctive cobblestone morphology. These cells are phenotypically similar to endothelial cells and have been shown to create vessel-like structures in vitro and in vivo.[8][9]

Certain developmental cells may be similar to or the same as other endothelial progenitors, though not typically referred to as EPCs. Hemangioblasts (or their in vitro counterpart, blast - colony forming cells) are cells believed to give rise to both the endothelial and hematopoietic systems during early development. Angioblasts are believed to be a form of early progenitor or stem cell which gives rise to the endothelium alone. More recently, mesoangioblasts have been theorized as a cell giving rise to multiple mesodermal tissues.[14][15][16]

Endothelial progenitor cells are likely important in tumour growth and are thought to be critical for metastasis and the angiogenesis.[17][18] A large amount of research has been done on CFU-Hill bone marrow-derived putative EPCs. Ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumour growth and vasculature development. This indicates that endothelial progenitor cells present novel therapeutic targets.[19]Inhibitor of DNA Binding 1 (ID1) has been used as a marker for these cells;[20] this allows for tracking EPCs from the bone marrow to the blood to the tumour-stroma and even incorporated in tumour vasculature.

Recently it has been found that miRNAs regulate EPC biology and tumour angiogenesis. This work by Plummer et al. found that in particular targeting of the miRNAs miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth by decreasing the mobilization of proangiogenic EPCs to the tumour. These findings indicate that directed targeting these miRNAs in EPCs may result in a novel strategy for inhibiting tumor angiogenesis.[21]

Studies have shown ECFCs and human umbilical vein endothelial cells (HUVECs) to have a capacity for tumor migration and neoangiogenesis even greater than that of other CD34+ hematopoietic cells when implanted in immunodeficient mice, suggesting the endothelial progenitors play a key role, but further supporting the importance of both cell types as targets for pharmacological therapy.[22]

Higher levels of circulating "endothelial progenitor cells" were detected in the bloodstream of patients, predicted better outcomes, and patients experienced fewer repeat heart attacks,[23] though statistical correlations between these outcomes and circulating endothelial progenitor cell numbers were scant in the original research. Endothelial progenitor cells are mobilized after a myocardial infarction, and that they function to restore the lining of blood vessels that are damaged during the heart attack.

A number of small phase clinical trials have begun to point to EPCs as a potential treatment for various cardiovascular diseases (CVDs). For instance, the year long "Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction" (TOPCARE-AMI) studied the therapeutic effect of infusing ex-vivo expanded bone marrow EPCs and culture enriched EPCs derived from peripheral blood into 20 patients suffering from acute myocardial infarction (MI). After four months, significant enhancements were found in ventricular ejection fraction, cardiac geometry, coronary blood flow reserve, and myocardial viability (Shantsila, Watson, & Lip). A similar study looked at the therapeutic effects of EPCs on leg ischemia caused by severe peripheral artery disease. The study injected a sample of EPC rich blood into the gastrocnemius muscles of 25 patients. After 24 weeks an increased number of collateral vessels and improved recovery in blood perfusion was observed. Rest pain and pain-free walking were also noted to have improved [24]

The role of endothelial progenitor cells in wound healing remains unclear. Blood vessels have been seen entering ischemic tissue in a process driven by mechanically forced ingress of existing capillaries into the avascular region, and importantly, instead of through sprouting angiogenesis. These observations contradict sprouting angiogenesis driven by EPCs. Taken together with the inability to find bone-marrow derived endothelium in new vasculature, there is now little material support for postnatal vasculogenesis. Instead, angiogenesis is likely driven by a process of physical force.[25]

In endometriosis, it appears that up to 37% of the microvascular endothelium of the ectopic endometrial tissue originates from endothelial progenitor cells.[26]

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Endothelial progenitor cell - Wikipedia

How Yogurt Science Could Lead To A Cure For Sickle Cell Anemia – WBUR

By Uncategorized

wbur Commentary

April 28, 2017

By Dr. Julie Losman

Dr. Julie Losman, a physician-scientist at Dana-Farber Cancer Institute and Brigham and Womens Hospital, told a memorable tale of sickle cell anemia and science at a Harvard rally before Boston's March for Science. It echoed a common theme, that support for basic science is crucial because it's not clear where the next great cure will come from. Her speech, lightly edited:

Sickle cell anemia has a very special place in the history of medicine: It was the first human disease that was understood on a molecular level.

Sickle cell anemia is caused by a single mutation in a gene, the hemoglobin gene, that produces a mutant protein with an abnormal structure. This abnormal hemoglobin disrupts the function of red blood cells.

The mutation was discovered in 1949 by a scientist named Linus Pauling. Pauling was not a medical doctor. He was a chemical engineer, a basic scientist. In fact, he won the Nobel Prize in 1954 for helping to invent the field of quantum chemistry, which is the study of how atoms and molecules interact. He was as fundamental and "basic" a scientist as you can be.

And yet it was Pauling's work on how small molecules bond together that led him to study how very big molecules, like proteins, bond together. This, in turn, led him to try and understand how a mutation in a gene could change the structure of a protein and alter the way that the protein bonds to other proteins.

That is how a chemical engineer who began his career studying protons and electrons made the first discovery of a human disease caused by a specific mutation.

The importance of this discovery to modern medicine cannot be overstated. Linus Paulings work laid the foundation for the entire field of medical genetics, which has absolutely revolutionized how we think about human disease.

For many, many, years, and even today, for many, many patients, the treatment for sickle cell anemia is palliative: Avoid things that trigger pain crises, treat pain crises when they happen, and try to protect organs from the damage that a crisis can cause. That is basically it.

A very few people with sickle cell anemia have successfully been cured with a transplant. Stem cell transplants are complicated, dangerous and very, very expensive. Undergoing a stem cell transplant requires absolute dedication from the patient, their families, their friends, their communities and their medical teams. Unfortunately, not everyone with sickle cell anemia has that kind of support or the access to exceptional medical care. A stem cell transplant for them is simply not an option.

But there is basic research going on right now --here in Boston and in labs across the United States and around the world --that has the potential to revolutionize how we treat sickle cell anemia. Right now, scientists are working on how to use an extraordinary new discovery called CRISPR to fix genetic mutations like the mutation that causes sickle cell anemia.

When this technique is perfected --not if it is perfected, but when it is perfected --it will be possible to take the stem cells of a patient, correct their mutation, and give them back their own stem cells. Because these reinfused stem cells would be perfectly at home in the patients body, there would be no need for months and months of post-transplant recovery.

Instead of being a leap of faith, a transplant would be a simple and safe procedure. It could even be done in young children with sickle cell anemia, before they ever have their first excruciating pain crisis.

The discovery of CRISPR and gene editing was not made by a geneticist or a stem cell biologist. CRISPR was discovered by a bunch of microbiologists, scientists who study bacteria and viruses.

In fact, much of the foundational work in CRISPR was done by nutritional microbiologists who wanted to understand how the bacteria we use to make cheese and yogurt are able to fight off viral infections. Imagine that! The future of gene therapy began in a yogurt vat.

The lesson we need to take away from Linus Pauling and these yogurt scientists is that basic fundamental research --the kind of research that is being done not just by the National Institutes of Health, but also by the National Science Foundation, the Department of Energy, NASA, the Environmental Protection Agency, the Department of Defense --is all absolutely crucial to advancing human health.

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How Yogurt Science Could Lead To A Cure For Sickle Cell Anemia - WBUR

Are baby, wisdom teeth the next wave in stem cell treatment? – wtkr.com

By Stem Cell Treatment

wtkr.com
Are baby, wisdom teeth the next wave in stem cell treatment?
wtkr.com
Research is still mostly in the experimental (preclinical) phase, said Ben Scheven, senior lecturer in oral cell biology in the school of dentistry at the University of Birmingham. Still, he said, dental stem cells may provide an advantageous cell ...

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Are baby, wisdom teeth the next wave in stem cell treatment? - wtkr.com

Stem cell therapy ‘magic’ for stroke, eye ailments – Vanguard

By Stem Cell Treatment

By David Ikudayisi

In recently published papers in the New England Journal of Medicine about the use of Stem Cell Therapy for Macular Degeneration, one report showed that 3 partially blind women became blind after the treatment with stem cells and the other report showed that an inevitable loss of vision was halted by use of stem cells in another patient. The stem cells used in these two reports were from two different sources fat and skin cells.

First of all, we need to remember or understand that Macular Degeneration is caused by the deterioration of the central portion of the retina, known as the macula, and it is responsible for focusing central vision in the eye, and it controls our ability to read, drive a car, recognize faces or colors, and see objects in fine detail. In America, it affects more than 10 million people more than cataracts and glaucoma combined.

Caucasians are more likely to develop the disease than African-Americans, Hispanics/Latinos or Africans. At present, Macular Degeneration is considered an incurable eye disease, and the closest hope for cure seems to be via Stem Cell Therapy. As shown in the reports, there is still a lot to be understood about stem cells in terms of dosing, frequency, source to be used for different disorders, etc; especially when talking about very sensitive organs of the body like the eyes.

The Florida Company that treated the three patients that went from partial blindness to total blindness have treated over 7,000 patients and have had very few adverse events reported. The scientific director of the company believes the safety track record is very strong and feels very confident about the procedures that they do as it has shown great success in many different health problems.

However, the rarity of the procedure causing harm draws me to see the many benefits and potential Adult Stem Cell Therapy could have on people. Examples of its effectiveness has been seen in so many patients in different studies and even in my own practice in the United States of America. There are already beneficiaries of Adult Stem Cell Therapy in Nigeria. I can say that my experience using stem cells have been great.

In fact, of all the patients that I have treated, only one did not respond positively after just 1 treatment. This was not even done with Adult Stem Cell Therapy but Platelet Rich Plasma (PRP) Therapy using the patients own blood. Nevertheless, there was no adverse event. The patient is recommended to do Adult Stem Cell Therapy which will increase his chance of success. Many of the other patients showed improvements after the first treatment, and the few that needed second treatment went on to see amazing results after more treatment was done; needless to say that they were elated with the results.

Generally, Adult Stem Cell Therapy and Platelet Rich Plasma Therapy are safe as shown by many published research reports and clinical trials done already. However, this does not guarantee that adverse effects cant occur as seen in the case of the 3 women who had accelerated blindness 2 years ago (as with any other treatments in the scope of medicine).

Another recent report in March 2017 from Medical College of Georgia at Augusta University in USA highlighted one of the benefits of Adult Stem Cell Therapy in stroke patients. The multicenter trial shows that not only was it safe, but if Adult Stem Cell Therapy is given within two days of an ischemic stroke, it could reduce the death of cells around the strokes core that were also injured. The Nigerian government should get involved more and invest more in Regenerative Medicine as it will help improve the health status of the nation.

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Stem cell therapy 'magic' for stroke, eye ailments - Vanguard

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