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Regenerating orthopedic tissues within the human body

By Stem Cell Clinic

By combining a synthetic scaffolding material with gene delivery techniques, researchers at Duke University are getting closer to being able to generate replacement cartilage where it's needed in the body.

Performing tissue repair with stem cells typically requires applying copious amounts of growth factor proteins -- a task that is very expensive and becomes challenging once the developing material is implanted within a body. In a new study, however, Duke researchers found a way around this limitation by genetically altering the stem cells to make the necessary growth factors all on their own.

They incorporated viruses used to deliver gene therapy to the stem cells into a synthetic material that serves as a template for tissue growth. The resulting material is like a computer; the scaffold provides the hardware and the virus provides the software that programs the stem cells to produce the desired tissue.

The study appears online the week of Feb. 17 in the Proceedings of the National Academy of Sciences.

Farshid Guilak, director of orthopaedic research at Duke University Medical Center, has spent years developing biodegradable synthetic scaffolding that mimics the mechanical properties of cartilage. One challenge he and all biomedical researchers face is getting stem cells to form cartilage within and around the scaffolding, especially after it is implanted into a living being.

The traditional approach has been to introduce growth factor proteins, which signal the stem cells to differentiate into cartilage. Once the process is under way, the growing cartilage can be implanted where needed.

"But a major limitation in engineering tissue replacements has been the difficulty in delivering growth factors to the stem cells once they are implanted in the body," said Guilak, who is also a professor in Duke's Department of Biomedical Engineering. "There's a limited amount of growth factor that you can put into the scaffolding, and once it's released, it's all gone. We need a method for long-term delivery of growth factors, and that's where the gene therapy comes in."

For ideas on how to solve this problem, Guilak turned to his colleague Charles Gersbach, an assistant professor of biomedical engineering and an expert in gene therapy. Gersbach proposed introducing new genes into the stem cells so that they produce the necessary growth factors themselves.

But the conventional methods for gene therapy are complex and difficult to translate into a strategy that would be feasible as a commercial product.

This type of gene therapy generally requires gathering stem cells, modifying them with a virus that transfers the new genes, culturing the resulting genetically altered stem cells until they reach a critical mass, applying them to the synthetic cartilage scaffolding and, finally, implanting it into the body.

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Regenerating orthopedic tissues within the human body

Deep TCR sequencing reveals extensive renewal of the T cell repertoire following autologous stem cell transplant in MS

By Uncategorized

A new study describes the complexity of the new T cell repertoire following immune-depleting therapy to treat multiple sclerosis, improving our understanding of immune tolerance and clinical outcomes.

In the Immune Tolerance Network's (ITN) HALT-MS study, 24 patients with relapsing, remitting multiple sclerosis received high-dose immunosuppression followed by a transplant of their own stem cells, called an autologous stem cell transplant, to potentially reprogram the immune system so that it stops attacking the brain and spinal cord. Data published in the Journal of Clinical Investigation quantified and characterized T cell populations following this aggressive regimen to understand how the reconstituting immune system is related to patient outcomes.

ITN investigators used a high-throughput, deep-sequencing technology (Adaptive Biotechnologies, ImmunoSEQTM Platform) to analyze the T cell receptor (TCR) sequences in CD4+ and CD8+ cells to compare the repertoire at baseline pre-transplant, two months post-transplant and 12 months post-transplant.

Using this approach, alongside conventional flow cytometry, the investigators found that CD4+ and CD8+ lymphocytes exhibit different reconstitution patterns following transplantation. The scientists observed that the dominant CD8+ T cell clones present at baseline were expanded at 12 months post-transplant, suggesting these clones were not effectively eradicated during treatment. In contrast, the dominant CD4+ T cell clones present at baseline were undetectable at 12 months, and the reconstituted CD4+ T cell repertoire was predominantly composed of new clones.

The results also suggest the possibility that differences in repertoire diversity early in the reconstitution process might be associated with clinical outcomes. Nineteen patients who responded to treatment had a more diverse repertoire two months following transplant compared to four patients who did not respond. Despite the low number of non-responders, these comparisons approached statistical significance and point to the possibility that complexity in the T cell compartment may be important for establishing immune tolerance.

This is one of the first studies to quantitatively compare the baseline T cell repertoire with the reconstituted repertoire following autologous stem cell transplant, and provides a previously unseen in-depth analysis of how the immune system reconstitutes itself following immune-depleting therapy.

About The Immune Tolerance Network

The Immune Tolerance Network (ITN) is a research consortium sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. The ITN develops and conducts clinical and mechanistic studies of immune tolerance therapies designed to prevent disease-causing immune responses, without compromising the natural protective properties of the immune system. Visit http://www.immunetolerance.org for more information.

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The above story is based on materials provided by Immune Tolerance Network. Note: Materials may be edited for content and length.

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Deep TCR sequencing reveals extensive renewal of the T cell repertoire following autologous stem cell transplant in MS

PROPOSED STEM CELL TREATMENT ON TRACK

By Stem Cell Treatment

By Bradley J. Fikes U-T 12:01 a.m.Feb. 19, 2014

A proposed Parkinsons disease treatment from stem cells is on track for an application to be filed with federal regulators around the start of 2015, International Stem Cell Corp. said Tuesday.

The Carlsbad company said the U.S. Food and Drug Administration had met with researchers for guidance on what steps need to be taken before filing an application.

The meeting went about as expected, said Simon Craw, executive vice president. Ongoing animal studies must be completed, along with safety testing. FDA officials discussed details, such as the number of animals to be tested and how the safety studies are to be conducted, Craw said.

International Stem Cells treatment consists of progenitor cells that mature into neural cells, including those making the neurotransmitter dopamine. These neurons are destroyed in the disease, causing progressive paralysis.

The progenitor cells are to be implanted into the brains of Parkinsons patients, where they are expected to make dopamine and protect the remaining dopamine-making neurons. They are derived from unfertilized, or parthenogenetic, human egg cells, made to grow without fertilization.

Interim data from tests in primates are expected in March, with final results later in the year. The Investigational New Drug application, or IND, is expected to be filed a short while thereafter, Craw said. Filing before years end would be a stretch, Craw said; the filing is more likely to take place in early 2015.

Shares of International Stem Cell closed Tuesday after the announcement at 24 cents, up 7 percent for the day.

The company is working with outside scientists, including D. Eugene Redmond Jr., who is leading a pharmacology/toxicology study. Parkinsons expert Mark Stacy at Duke University will lead the clinical trial. Evan Y. Snyder, a stem cell expert at Sanford-Burnham Medical Research Institute, assists as a scientific adviser.

The companys approach is similar to one being studied by scientists at The Scripps Research Institute led by Jeanne Loring. Moreover, both are expected to ask approval to begin trials around the same time.

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PROPOSED STEM CELL TREATMENT ON TRACK

CardioCell begins 2 heart stem cell trials

By Stem Cell Treatment

CardioCell has begun two new clinical trials of its stem cell treatment for recent heart attack patients, the San Diego company said Wednesday.

A Phase 3 trial has started in Kazakhstan and a Phase 2a trial in the United States, said privately held CardioCell. The stem cells are grown under low oxygen conditions, similar to the natural environment of stem cells in the body, said cardiologist Stephen Epstein, a scientific advisor.

Stem cells grown under higher levels of oxygen common in laboratory environments act differently than those grown in low oxygen levels, which may reduce their regenerative abilities, said Epstein, director of translational and vascular biology research at MedStar Heart Institute in Washington, D.C. Moreover, these cells tolerate ischemia, a reduced blood supply that limits the availability of oxygen and nutrients. Since heart attacks are by definition caused by ischemia, that tolerance should help the cells survive long enough to help, Epstein said.

The stem cells appear to help by producing chemicals that stimulate heart regeneration, Epstein said.

The stem cells are of a type called mesenchymal, taken from bone marrow. They were produced by Stemedica, another San Diego stem cell company, which spun off CardioCell.

More information about the U.S. trial, including eligibility criteria, is available at utsandiego.com/cardiocell. More information about CardioCell is available at http://stemcardiocell.com.

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CardioCell begins 2 heart stem cell trials

Intl. Stem Cell readies for Parkinson's study

By Stem Cell Treatment

A proposed Parkinson's disease treatment from stem cells is on track for an application to be filed with federal regulators around the start of 2015, International Stem Cell Corp. said Tuesday.

The Carlsbad-based company said the U.S. Food and Drug Administration had met with researchers for guidance on what steps need to be taken before filing an application. The meeting went about as expected, said Simon Craw, executive vice president. Ongoing animal studies must be completed, along with safety testing. FDA officials discussed details such as the number of animals to be tested and how the safety studies are to be conducted, Craw said.

International Stem Cell's treatment consists of progenitor cells that mature into neural cells, including those making the neurotransmitter dopamine. These neurons are destroyed in the disease, causing progressive paralysis.

The progenitor cells are to be implanted into the brains of Parkinson's patients, where they are expected to make dopamine and protect the remaining dopamine-making neurons. They are derived from unfertilized, or parthenogenetic, human egg cells, made to grow without fertilization.

Human parthenogenetic neural stem cells in the process of differentiating into dopamine-producing neurons. / International Stem Cell Corp.

Interim data from tests in primates are expected in March, and final results later in the year. The Investigational New Drug application, or IND, is expected to be filed a short while thereafter, Craw said. Filing before year's end "would be a stretch," Craw said; the filing is more likely to take place in early 2015.

Shares of International Stem Cell closed Tuesday after the announcement at 24 cents, up 7 percent for the day. The company is working with outside scientists; including D. Eugene Redmond Jr., who is leading a pharmacology/toxicology study. Parkinson's expert Mark Stacy at Duke University will lead the clinical trial. Evan Y. Snyder, a stem cell expert at Sanford-Burnham Medical Research Institute, assists as a scientific advisor.

The company's approach is similar to one being studied by scientists at The Scripps Research Institute led by Jeanne Loring. Moreover, both are expected to ask approval to begin trials around the same time.

Loring's group gets its cells from the patients to be treated, "reprogrammed" back to an embryonic-like state and called induced pluripotent stem cells, then differentiated into the neural progenitor cells. That treatment's main advantage is the use of the patients' own or autologous cells, expected to minimize any possible immune reaction.

The two groups know each other. Craw said International Stem Cell has hired some of Loring's students, and they have collaborated on some research.

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Intl. Stem Cell readies for Parkinson's study

Acid-Bath Stem Cell Study under Investigation

By Stem Cell Treatment

A research institute is launching an inquiry after allegations of irregularities in two blockbuster papers

The controversial work involved a mouse embryo injected with cells made pluripotent through stress. Credit:Haruko Obokata

A leading Japanese research institute has opened an investigation into a groundbreaking stem-cell study after concerns were raised about its credibility.

The RIKEN center in Kobe announced on Friday that it is looking into alleged irregularities in the work of biologist Haruko Obokata, who works at the institution. She shot to fame last month as the lead author on two paperspublished inNature that demonstrated a simple way to reprogram mature mice cells into an embryonic state by simply applying stress, such as exposure to acid or physical pressure on cell membranes. The RIKEN investigation follows allegations on blog sites about the use of duplicated images in Obokatas papers, and numerous failed attempts to replicate her results.

Cells in an embryonic state can turn into the various types of cells that make up the body, and are therefore an ideal source of patient-specific cells. They can be used to study the development of disease or the effectiveness of drugs and could also be transplanted to regenerate failing organs. A consistent and straightforward path to reprogramming mature cells was first demonstrated in 2006, when a study showed that the introduction of four genes could switch the cells into an embryonic form known as induced pluripotent stem (iPS) cells. The introduction of genes, however, introduces uncertainties about the fidelity of the cells, and Obokatas reports that the feat could be done so simply were met with awe, and a degree of scepticism (see 'Acid bath offers easy path to stem cells').

That scepticism deepened last week when blogs such asPubPeer started noting what seem to be problems in the twoNaturepapers and in an earlier paper from 2011, which relates to the potential of stem cells in adult tissues. In the 2011 paper, on which Obokata is first author, a figure showing bars meant to prove the presence of a certain stem-cell marker appears to have been inverted and then used to show the presence of a different stem-cell marker. A part of that same image appears in a different figure indicating yet another stem-cell marker. The paper contains another apparent unrelated duplication.

The corresponding author of that study, Charles Vacanti, an anaesthesiologist at Harvard Medical School in Boston, toldNaturethat he learned only last week of a mix up of some panels. He has already contacted the journal to request a correction. It certainly appears to have been an honest mistake [that] did not affect any of the data, the conclusions or any other component of the paper, says Vacanti.

The problems in the two recentNaturepapers, on both of which Obokata is a corresponding author (Vacanti is a co-author on both, and corresponding author on one), also relate to images. In one paper, one of the sections in a genomic analysis in the first figure appears to be spliced in. In the other paper, images of two placentas meant to be from different experiments look strikingly similar.

Teruhiko Wakayama, a cloning specialist at Yamanashi University in Yamanashi prefecture, is a co-author on both of the papers and took most of the placental images. He admits that the two look similar but says it may be a case of simple confusion. Wakayama, who left RIKEN during the preparation of the manuscript, says he sent more than a hundred images to Obokata and suggests that there was confusion over which to use. He says he is now looking into the problem.

The scepticism has been inflamed by reports of difficulty in reproducing Obakatas latest results. None of ten prominent stem-cell scientists who responded to a questionnaire fromNaturehas had success. A blog soliciting reports from scientists in the fieldreports eight failures. But most of those attempts did not use the same types of cells that Obokata used.

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Acid-Bath Stem Cell Study under Investigation

Human stem cell research: all viewpoints

By Stell Cell Research

Sponsored link.

Stem cells are a special form of human life: they are alive and contain human DNA. They have a unique feature in that they can be coaxed into developing into some or all of the 220 cell types found in the human body. Eventually, stem cells may be routinely used by doctors to generate new organs or new replacement body parts for people: They might become a new pancreas to cure a person with diabetes, or new nerve cells to cure a paralized person, etc.

There are three types of stem cells:

"...reprogrammed a dozen cell types, including those from the brain, skin, lung and liver, hinting that the method will work with most, if not all, cell types. On average, she says, 25% of the cells survive the stress and 30% of those convert to pluripotent cells already a higher proportion than the roughly 1% conversion rate of iPS cells." 1

The National Institutes of Health web site states:

"To realize the promise of novel cell-based therapies for such pervasive and debilitating diseases, scientists must be able to manipulate stem cells so that they possess the necessary characteristics for successful differentiation, transplantation, and engraftment. The following is a list of steps in successful cell-based treatments that scientists will have to learn to control to bring such treatments to the clinic. To be useful for transplant purposes, stem cells must be reproducibly made to:

Also, to avoid the problem of immune rejection, scientists are experimenting with different research strategies to generate tissues that will not be rejected.

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Human stem cell research: all viewpoints

Doctors use stem cell therapy to treat lung diseases …

By Stem Cell Doctors

Tampa, Florida --It's the third leading cause of death in the U.S.You've probably even seen ads for treating COPD, but you may not even know what it is.

Chronic Obstructive Pulmonary Disease is a progressive lung disease likely caused by smoking, but air pollution can also be a factor. According to the American Lung Association, women are 37 percent more likely to have it than men and since there's no cure, people will do anything to breathe a little easier.

Doctors atthe Lung Institute in Tampa are using a lung patient's own stem cells to help treat COPD, emphysema and pulmonary fibrosis byrepairing damaged tissue. Like most patients seeking help, 70-year-old Daniel Odulio depends on an oxygen tank. He flew here all the way from The Philippines to improve his life.

The Lung Institute told 10 News the doctorsuse thelatest FDA-approved commercially available equipment for collecting and isolating stem cells using patients' own blood and adipose fat. They say theinnovative stem cell therapy won't be rejected because the doctors use the patients' own cells.In some cases, patients are able to get rid of their oxygen tanks altogether.

10 News

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Doctors use stem cell therapy to treat lung diseases ...

Older Muscle Stem Cells Rejuvenated to Function Like Younger Cells, May Help Elderly Repair Muscle

By Stem Cell Medicine

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Health & Medicine for Senior Citizens

Older Muscle Stem Cells Rejuvenated to Function Like Younger Cells, May Help Elderly Repair Muscle

Stanford researchers pinpoint why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury

By Krista Conger

Feb. 17, 2014 - Researchers at the Stanford University School of Medicine have pinpointed why normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury: Over time, stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew.

In the past, its been thought that muscle stem cells themselves dont change with age, and that any loss of function is primarily due to external factors in the cells environment, said Helen Blau, PhD, the Donald and Delia B. Baxter Foundation Professor.

However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.

Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. Our findings identify a defect inherent to old muscle stem cells, she said. Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage.

Blau, a professor of microbiology and immunology and director of Stanfords Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, published online Feb. 16 in Nature Medicine. Postdoctoral scholar Benjamin Cosgrove, PhD, and former postdoctoral scholar Penney Gilbert, PhD, now an assistant professor at the University of Toronto, are the lead authors.

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Older Muscle Stem Cells Rejuvenated to Function Like Younger Cells, May Help Elderly Repair Muscle

Scientists 'rejuventate' stem cells in elderly mice to repair muscles

By Stem Cell Medicine

PALO ALTO, Calif., Feb. 17 (UPI) -- In an experiment with mice, U.S. scientists say they've enabled muscle recovery in elderly mice by rejuvenating stem cells within their muscle tissue.

Normal aging is accompanied by a diminished ability to regain strength and mobility after muscle injury because over time stem cells within muscle tissues dedicated to repairing damage become less able to generate new muscle fibers and struggle to self-renew, researchers at Stanford University reported Sunday.

"In the past, it's been thought that muscle stem cells themselves don't change with age, and that any loss of function is primarily due to external factors in the cells' environment," Helen Blau of the university's school of medicine said.."However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles."

However, Blau and her colleagues say they've identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells.

"Our findings identify a defect inherent to old muscle stem cells," she said. "Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage."

The researchers used drugs to block elevated biological activity within the stem cells that causes them to degenerate into non-stem, muscle progenitor cells.

When transplanted back into the animal, the treated, rejuvenated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair, they researchers said.

"In mice, we can take cells from an old animal, treat them for seven days -- during which time their numbers expand dramatically, as much as 60-fold -- and then return them to injured muscles in old animals to facilitate their repair," Blau said.

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Scientists 'rejuventate' stem cells in elderly mice to repair muscles

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