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Scientists Develop Pioneering Method to Define Stages of Stem Cell Reprogramming

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Newswise In a groundbreaking study that provides scientists with a critical new understanding of stem cell development and its role in disease, UCLA researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research led by Dr. Kathrin Plath, professor of biological chemistry, have established a first-of-its-kind methodology that defines the unique stages by which specialized cells are reprogrammed into stem cells that resemble those found in the embryo.

The study was published online ahead of print in the journal Cell.

Induced pluripotent stem cells (known as iPSCs) are similar to human embryonic stem cells in that both cell types have the unique ability to self-renew and have the flexibility to become any cell in the human body. iPSC cells, however, are generated by reprogramming skin or blood cells and do not require an embryo.

Reprogramming is a long process (about one to two weeks) and largely inefficient, with typically less than one percent of the primary skin or blood cells successfully completing the journey to becoming an iPSC. The exact stages a cell goes through during the reprogramming process are also not well understood. This knowledge is important, as iPSCs hold great promise in the field of regenerative medicine, as they can provide a single source of patient-specific cells to replace those lost to injury or disease. They can also be used to create novel disease models from which new drugs and therapies can be developed.

This research has broad impact, because by deepening our understanding of cell reprogramming we have the potential to improve disease modeling and the generation of better sources of patient-specific specialized cells suitable for replacement therapy, said Plath. This can ultimately benefit patients with new and better treatments for a wide range of diseases.

Drs. Vincent Pasque and Jason Tchieu, postdoctoral fellows in the lab of Dr. Plath and co-first authors of the study, developed a roadmap of the reprogramming process using detailed time-course analyses. They induced the reprogramming of skin cells into iPSC, then observed and analyzed on a daily basis or every other day the process of transformation at the single-cell level. The data were collected and recorded over a period of up to two weeks.

Plaths team found that the changes that happen in cells during reprogramming occur in a sequential stage-by-stage manner, and that importantly, the stages were the same across all the different reprogramming systems and different cell types analyzed.

The exact stage of reprogramming of any cell can now be determined, said Pasque. This study signals a big change in thinking, because it provides simple and efficient tools for scientists to study stem cell creation in a stage-by-stage manner. Most studies to date ignore the stages of reprogramming, but we can now seek to better understand the entire process on both a macro and micro level.

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Scientists Develop Pioneering Method to Define Stages of Stem Cell Reprogramming

Pioneering method developed to define stages of stem cell reprogramming

By Uncategorized

In a groundbreaking study that provides scientists with a critical new understanding of stem cell development and its role in disease, UCLA researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research led by Dr. Kathrin Plath, professor of biological chemistry, have established a first-of-its-kind methodology that defines the unique stages by which specialized cells are reprogrammed into stem cells that resemble those found in the embryo.

The study was published online ahead of print in the journal Cell.

Induced pluripotent stem cells (known as iPSCs) are similar to human embryonic stem cells in that both cell types have the unique ability to self-renew and have the flexibility to become any cell in the human body. iPSC cells, however, are generated by reprogramming skin or blood cells and do not require an embryo.

Reprogramming is a long process (about one to two weeks) and largely inefficient, with typically less than one percent of the primary skin or blood cells successfully completing the journey to becoming an iPSC. The exact stages a cell goes through during the reprogramming process are also not well understood. This knowledge is important, as iPSCs hold great promise in the field of regenerative medicine, as they can provide a single source of patient-specific cells to replace those lost to injury or disease. They can also be used to create novel disease models from which new drugs and therapies can be developed.

"This research has broad impact, because by deepening our understanding of cell reprogramming we have the potential to improve disease modeling and the generation of better sources of patient-specific specialized cells suitable for replacement therapy," said Plath. "This can ultimately benefit patients with new and better treatments for a wide range of diseases.

Drs. Vincent Pasque and Jason Tchieu, postdoctoral fellows in the lab of Dr. Plath and co-first authors of the study, developed a roadmap of the reprogramming process using detailed time-course analyses. They induced the reprogramming of skin cells into iPSC, then observed and analyzed on a daily basis or every other day the process of transformation at the single-cell level. The data were collected and recorded over a period of up to two weeks.

Plath's team found that the changes that happen in cells during reprogramming occur in a sequential stage-by-stage manner, and that importantly, the stages were the same across all the different reprogramming systems and different cell types analyzed.

"The exact stage of reprogramming of any cell can now be determined," said Pasque. "This study signals a big change in thinking, because it provides simple and efficient tools for scientists to study stem cell creation in a stage-by-stage manner. Most studies to date ignore the stages of reprogramming, but we can now seek to better understand the entire process on both a macro and micro level."

Plath's team further discovered that the stages of reprogramming to iPSC are different from what was expected. They found that it is not simply the reversed sequence of stages of embryo development. Some steps are reversed in the expected order; others do not actually happen in the exact reverse order and resist a change until late during reprogramming to iPSCs.

"This reflects how cells do not like to change from one specialized cell type to another and resist a change in cell identity," said Pasque. "Resistance to reprogramming also helps to explain why reprogramming takes place only in a very small proportion of the starting cells."

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Pioneering method developed to define stages of stem cell reprogramming

Brainstorm Stem-Cell Therapy Continues to Show Treatment Effect in ALS Patients

By Stem Cell Treatment

By: Adam Feuerstein | 01/05/15 - 10:52 AM EST

Once injected, the NurOwn stem cells bathe the damaged neurons of ALS patients with secretions of nerve growth factors. Brainstorm has a home run on its hands if NurOwn can be shown to slow or halt the progressive destruction of neurons, and if that disease-modifying effect translates into improved muscle function for ALS patients. Monday's update comes from a Phase IIa trial in which 14 ALS patientswere followed for the three months without treatment. At month four, each patient wastransplanted with their own personalized NurOwn therapy and then assessed every month for six months. Brainstorm evaluated NurOwn's impact on ALS disease progression using the ALSFRS score, a commonly used assessment of treatment response and muscle function in ALS patients. Lung function, another commonly used measure of efficacy in ALS clinical trials, was also measured.

Twelve ALS patients were evaluable for response. Of these, 11 patientsshowed aslowing of ALS disease progression at six months compared to baseline, measured either by improved ALSFRS or lung function scores, Brainstorm said. Two other patients enrolled in the study died. Administration of the NurOwn therapy was well tolerated by patients, the company said.

The final Phase IIa data announced Monday were a small improvement over interim results from the same study presented last June. Further, detailed data from the study will be presented at a medical meeting later this year. For perspective purposes, it's important to note that this phase IIa study enrolled a relatively small number of ALS patients and was conducted at a single hospital in Israel. This doesn't necessarily discredit the positive results, but conclusions about NurOwn's ultimate benefit as an ALS therapy can't be drawnuntil data from larger studies are gathered.

Brainstorm is conducting another, larger Phase II study in the U.S., enrolling 48 ALS patients who will be randomized 3:1 to receive a single NurOwn treatment in the muscle and spine, or a placebo treatment. The study is being conducted at two hospitals in Massachusetts, UMass Medical Center and Massachusetts General, and the Minnesota-based Mayo Clinic. The study's primary endpoint is the safety and tolerability of NurOwn, but investigators will also assess ALS patients for efficacy using measures of ALS disease activity and muscle function. The first patient was enrolled into the Phase II study last June and Brainstorm expects results to be ready in the first half of 2016.

The company is also in the planning stages for another Phase II study in which ALS patients will be treated with multiple doses of NurOwn. Must Read: 11 Best Small-Cap Technology Stocks That Could Hit It Big in 2015

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Brainstorm Stem-Cell Therapy Continues to Show Treatment Effect in ALS Patients

Restore and Regenerate

By Stem Cell Treatment

Some people say that osteoarthritis, cartilage degradation, and chronic joint pains degenerative diseases associated with agingare conditions with no cure, but Dr. Charlie Poblete and Dr. Jae Pak say otherwise.

It is a new era of medicine, opens Dr. Jae Pak, one of Koreas premier orthopedic stem cell surgeons and a visiting expert consultant of the Stem Care Orthopedics Department under Aivee Institute (AI). He was recently in the country to shed light on stem cell therapy and how it offers more accessible treament options for patients suffering from degenerative orthopedic conditions.

Dr. Pak was joined by Dr. Charlie Poblete, one of the countrys leading orthopedic surgeon who has a special interest on regenerative medicine and stem cells. Incidentally, Dr. Poblete is the head of the Stem Care Orthopedic Department of AI. Stem cells are not really part of alternative medicine. Its part of a modern medicine because we are talking about the biochemistry that goes on in the body with stem cell treatment, Dr. Charlie relates while adding, the good thing about medicine nowadays is its starting to look at the molecular aspect of the body, the molecular and cellular side of medicine.

Over the years, stem cell therapy has been touted as one procedure that can heal multitude of bone, cartilage, and joint ailments. Stem cells are the bodys natural healing cells. They are recruited by chemical signals emitted by damaged tissues to repair and regenerate the damaged cells. Stem cells derived from an individuals tissues may well be the next major development in medicine. In the right environment, these stem cells can change into bone, cartilage, muscle, fat, collagen, neural tissue, blood vessels, and even some organs. Stem cells may also effect healing by secreting special chemical messengers that repair damaged tissue.

There are many clinical conditions that benefits from stem cell therapy: heart attack patients have shown quicker healing period, improved condition for patients with multiple sclerosis, muscular dystrophy, Parkinsons disease, ALS, and stroke. Stem cells may also be effective in the treatment of macular degeneration, Crohns disease, and numerous pulmonary conditions. Also, stem cells are now used for patients with kidney failure and in the treatment of critical limb ischemia.

Stem Cell therapy is a simple procedure. Fat is aspirated from the tummy or the thighs, and then we separate the stem cells from them. It is then activated and injected into joints to restore and regenerate, explains Dr. Jae.

Stem Care by The Aivee Group is the countrys pioneer in advanced Autologous Stem Cell Therapy with an esteemed orthopedic team of doctors and surgeons regarded with international qualifications. The institute, with its CEO and medical director Dr. Z. Teo, together with his wife dermatologist Dr. Aivee Teo, now features a stronger multifaceted protocol in treating orthopedic ailments with a faster rate of positive patient response. They are also adept in complimentary therapies to further intensify the restorative powers of stem cells through the effective use of Growth Factors, Shockwave, Radio Frequency, and Electro Magnetic Therapies. 4033245, 4031982, 09209665613, 09175210222. http://www.stemcareinstitute.com

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Restore and Regenerate

The Irvine Stem Cell Treatment Center Announces Adult Stem Cell Public Seminars in Orange County, California

By Stem Cell Treatment

Seal Beach, Laguna Hills, and Lake Forest, California (PRWEB) January 05, 2015

The Irvine Stem Cell Treatment Center announces a series of free public seminars on the use of adult stem cells for various degenerative and inflammatory conditions. They will be provided by Dr. Thomas A. Gionis, Surgeon-in-Chief.

The seminars will be held on Sunday, January 11, 2015, at 2:30pm and 4:30pm at Marie Callenders Grill, 12489 Seal Beach Blvd., Seal Beach, CA 90740; Tuesday, January 13, 2015, at 2:00pm and 4:00pm at Pollys Pies, 23701 Moulton Parkway, Laguna Hills, CA 92653; Friday, January 16, 2015, at 1:30pm and 3:30pm at Marie Callenders Grill, 12489 Seal Beach Blvd., Seal Beach, CA 90740; Saturday, January 17, 2015, at 2:30pm and 4:30pm at Dennys Restaurant, 23515 El Toro Road, Lake Forest, CA 92630. Please RSVP at (949) 679-3889.

The Irvine Stem Cell Treatment Center, along with sister affiliates, the Miami Stem Cell Treatment Center and the Manhattan Regenerative Medicine Medical Group, abide by investigational protocols using adult adipose derived stem cells (ADSCs) which can be deployed to improve patients quality of life for a number of chronic, degenerative and inflammatory conditions and diseases. ADSCs are taken from the patients own adipose (fat) tissue (found within a cellular mixture called stromal vascular fraction (SVF)). ADSCs are exceptionally abundant in adipose tissue. The adipose tissue is obtained from the patient during a 15 minute mini-liposuction performed under local anesthesia in the doctors office. SVF is a protein-rich solution containing mononuclear cell lines (predominantly adult autologous mesenchymal stem cells), macrophage cells, endothelial cells, red blood cells, and important Growth Factors that facilitate the stem cell process and promote their activity.

ADSCs are the body's natural healing cells - they are recruited by chemical signals emitted by damaged tissues to repair and regenerate the bodys injured cells. The Irvine Stem Cell Treatment Center only uses Adult Autologous Stem Cells from a persons own fat No embryonic stem cells are used. Current areas of study include: Emphysema, COPD, Asthma, Heart Failure, Parkinsons Disease, Stroke, Multiple Sclerosis, Lupus, Rheumatoid Arthritis, Crohns Disease, and degenerative orthopedic joint conditions. For more information, or if someone thinks they may be a candidate for one of the adult stem cell protocols offered by the Irvine Stem Cell Treatment Center, they may contact Dr. Gionis directly at (949) 679-3889, or see a complete list of the Centers study areas at: http://www.IrvineStemCellsUSA.com.

About the Irvine Stem Cell Treatment Center: The Irvine Stem Cell Treatment Center, along with sister affiliates, the Miami Stem Cell Treatment Center and the Manhattan Regenerative Medicine Medical Group, is an affiliate of the Cell Surgical Network (CSN); we are located in Irvine and Westlake, California. We provide care for people suffering from diseases that may be alleviated by access to adult stem cell based regenerative treatment. We utilize a fat transfer surgical technology to isolate and implant the patients own stem cells from a small quantity of fat harvested by a mini-liposuction on the same day. The investigational protocols utilized by the Irvine Stem Cell Treatment Center have been reviewed and approved by an IRB (Institutional Review Board) which is registered with the U.S. Department of Health, Office of Human Research Protection; and the study is registered with Clinicaltrials.gov, a service of the U.S. National Institutes of Health (NIH). For more information, visit our websites: http://www.IrvineStemCellsUSA.com, http://www.MiamiStemCellsUSA.com or http://www.NYStemCellsUSA.com.

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The Irvine Stem Cell Treatment Center Announces Adult Stem Cell Public Seminars in Orange County, California

Ten years in, California's stem cell program is getting a reboot

By Stem Cell Treatment

Turning 10 years old may not quite mark adolescence for a human child, but for a major government research effort such as California's stem cell program, it's well past middle age.

So it's a little strange to hear C. Randal Mills, the new president and chief executive of the program known formally as the California Institute for Regenerative Medicine, say it's time to instill in CIRM "a clear sense of mission."

But that's what Mills is planning for the coming year, as he launches CIRM 2.0, a comprehensive reboot of the program.

Mills, a former biotech company chief executive, took over as CIRM's president last May. His first task, he told me, was to "take a step back and look broadly at how we do our business." He reached the conclusion that "there was a lot of room for improvement."

That's a striking admission for a program that already has allocated roughly two-thirds of its original $3-billion endowment.

Biomedical researchers are sure to find a lot to like about CIRM 2.0, especially Mills' commitment to streamline the program's grant and loan approval process for projects aimed at clinical trials of potential therapies. Reviews of applications take about 22 months on average; Mills hopes to cut that to about three months. The process can be made more efficient without sacrificing science: "We need to do it quickly and also focus on quality," he says in a videotaped presentation on the CIRM website. The CIRM board last month approved a six-month, $50-million round of funding under the new system, all to be aimed at testing new therapies.

Yet the focus on drug development shows that CIRM remains a prisoner of the politics that brought it into existence. The Proposition 71 campaign in 2004 employed inflated promises of cures for Parkinson's disease, Alzheimer's, diabetes and other therapy-resistant conditions to goad California voters into approving the $3-billion bond issue ($6 billion with interest) for stem cell research.

CIRM says it has funded clinical trials of 10 therapies and has backed an additional 87 projects "in the later stages of moving toward clinical trials." In scientific terms that's progress, but it may fall short of the public expectations of "cures" stoked by the initiative's promoters 10 years ago.

And that poses a political problem. At its current rate of grant and loan approvals of about $190 million a year, CIRM has enough funding to last until 2020. What happens after that is an open question, but any campaign to seek new public funding may depend on CIRM's having a successful therapy to show off to voters.

Mills says winning approval for more public funding isn't the goal of CIRM 2.0. "It's not our job at CIRM to extend the life of CIRM," he told me. Instead, he couches the need for urgency in terms of serving patients. As chief executive of Maryland-based Osiris Therapeutics, where he worked before joining CIRM, he says, he had "a firsthand view into the significance of stem cell treatment, and of how important urgency is in this game." Osiris received approval from the Food and Drug Administration and Canadian regulators for a stem cell drug to treat children with severe complications from bone marrow and other blood transplants.

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Ten years in, California's stem cell program is getting a reboot

Scientists explain how stem cells and 'bad luck' cause cancer

By Stem Cell Doctors

Why are some types of cancer so much more common than others? Sometimes its due to faulty genes inherited from ones parents and sometimes to behaviors like smoking a pack of cigarettes every day. But in most cases, it comes down to something else stem cells.

This is the intriguing argument made by a pair of researchers from Johns Hopkins University. In a study published Friday in the journal Science, they found a very high correlation between the differences in risk for 31 kinds of cancer and the frequency with which different types of stem cells made copies of themselves.

Just how strong was this link? On a scale that goes from 0 (absolutely no correlation) to 1 (exact correlation), biostatistician Cristian Tomasetti and cancer geneticist Bert Vogelstein calculated that it was at least a 0.8. When it comes to cancer, thats high.

No other environmental or inherited factors are known to be correlated in this way across tumor types, Tomasetti and Vogelstein wrote.

Researchers have long recognized that when cells copy themselves, they sometimes make small errors in the billions of chemical letters that make up their DNA. Many of these mistakes are inconsequential, but others can cause cells to grow out of control. That is the beginning of cancer.

The odds of making a copying mistake are believed to be the same for all cells. But some kinds of cells copy themselves much more often than others. Tomasetti and Vogelstein hypothesized that the more frequently a type of cell made copies of itself, the greater the odds that it would develop cancer.

The pair focused on stem cells because of their outsized influence in the body. Stem cells can grow into many kinds of specialized cells, so if they contain damaged DNA, those mistakes can spread quickly.

The researchers combed through the scientific literature and found studies that described the frequency of stem cell division for 31 different tissue types. Then they used data from the National Cancer Institutes Surveillance, Epidemiology and End Results database to assess the lifetime cancer risk for each of those tissue types. When they plotted the total number of stem cell divisions against the lifetime cancer risk for each tissue, the result was 31 points clustered pretty tightly along a line.

To put this notion in concrete terms, consider the skin. The outermost layer of the skin is the epidermis, and the innermost layer of the epidermis contains a few types of cells. Basal epidermal cells are the ones that copy themselves frequently, with new cells pushing older ones to the skins surface. Melanocytes are charged with making melanin, the pigment that protects the skin from the suns damaging ultraviolet rays.

When sunlight hits bare skin, both basal epidermal cells and melanocytes get the same exposure to UV. But basal cell carcinoma is far more common than melanoma about 2.8 million Americans are diagnosed with basal cell carcinoma each year, compared with roughly 76,000 new cases of melanoma, according to the Skin Cancer Foundation. A major reason for this discrepancy, Tomasetti and Vogelstein wrote, is that epidermal stem cells divide once every 48 days, while melanocytes divide only once every 147 days.

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Scientists explain how stem cells and 'bad luck' cause cancer

Two-thirds of adult cancers largely down to bad luck rather than genes

By Stem Cell Medicine

Colon cancer cell. Colon tissue undergoes four times more stem cell divisions than small intestine tissue in humans, and is much more prevalent. Photograph: Micro Discovery/Corbis

Good luck, rather than good genes, may be the key reason why some people are protected from certain cancers while others develop the disease, according to a new study.

Two-thirds of adult cancers, say the researchers from the Johns Hopkins Kimmel Cancer Center in the United States, are caused by random mutation in the tissue cells during the ordinary process of stem cell division. In the other third, our genetic inheritance and lifestyles are the main factors.

The scientists have created a mathematical model which, they say, shows it is wrong to assume that there are such things as good genes that may prevent us getting cancer even though we smoke, drink heavily and carry excessive weight.

All cancers are caused by a combination of bad luck, the environment and heredity, and weve created a model that may help quantify how much of these three factors contribute to cancer development, says Bert Vogelstein, the Clayton professor of oncology at the Johns Hopkins University school of medicine and one of the authors of the paper published in the journal Science. Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their good genes, but the truth is that most of them simply had good luck.

The scientists looked at how often stem cell division, the normal process of cell renewal, takes place in 31 different tissue types, to find out whether the sheer number of divisions can lead to more mistakes or DNA mutations occurring. They did not look at tissues from two of the commonest forms of cancer breast and prostate which are known to have particular environmental triggers, such as obesity. These were not included because they could not find reliable data on the normal division rate of stem cells in these tissues.

Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue, said Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.

It could be argued, they say, that the colon is exposed to more environmental factors than the small intestine but they point out that the opposite is true for mice, which have more stem cell divisions and a higher rate of cancer in their small intestines than in their colon.

The scientists say that bad luck plays a stronger role in some cancers than in others. In two-thirds of the cancers 22 cancer types random mutations in genes that drive cancer could explain why the disease occurred. The other nine cancers occurred more often than the random mutation rate would predict, suggesting that inherited genes or lifestyle factors were the main cause. They included lung cancer, where smoking is the major cause, and skin cancer, which can be triggered by sun exposure.

Speaking on the BBC Radio 4 Today programme on Friday, co-author biomathematician Dr Cristian Tomasetti, also from Johns Hopkins University, said: Im not claiming any cancers, overall across the population, are the result of pure chance, but what I am claiming is there are some tissues for example blood cancer where there is very little evidence of any hereditary or environmental factor.

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Two-thirds of adult cancers largely down to bad luck rather than genes

Two-thirds of adult cancers largely due to bad luck, study suggests

By Stem Cell Medicine

Lifestyle choices and genetics are big risk factors for certain cancers, but a new study concludes that the majority of cancer incidence is due mostly to bad luck when our cells divide.

The study comes from scientists at the Johns Hopkins Kimmel Cancer Center who created a statistical model to measure the proportion of cancer cases that are caused mainly by random DNA mutations during stem cell division.

By their calculations, two-thirds of adult cancer incidents can be explained by bad luck when stem cells divide.

All cancers are caused by a combination of bad luck, the environment and heredity, says lead researcher Dr. Bert Vogelstein, a professor of oncology at the Johns Hopkins University School of Medicine.

"Weve created a model that may help quantify how much of these three factors contribute to cancer development, he said in a statement.

Cancer occurs when stem cells in tissues make random mistakes, or mutations, during the replication process in cell division. The more that these mutations accumulate, the higher the risk that cells will begin to grow, unchecked, into tumours.

But Vogelstein says it's never been clearly understood how much of a contribution these random mistakes made to cancer incidence, compared to genetic inheritance, lifestyle, or environmental factors.

So they focused on 31 tissue types, looking at the number of stem cell divisions in each cancer. They then compared these rates with lifetime cancer risk among the same cancer types in the American population.

Significantly, they did not include breast cancer and prostate cancer in their study, even though these are two of the most commonly diagnosed cancers among adults. The researchers explained that they could not find reliable stem cell division rates on these cancer types.

Of the 31 cancer types they did look at, they found that 22 could be largely explained by the bad luck factor of random DNA mutations during cell division.

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Two-thirds of adult cancers largely due to bad luck, study suggests

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