Stem Cell Clinic

Extensive renewal of the T cell repertoire following autologous stem cell transplant in MS

By Stem Cell Treatment

PUBLIC RELEASE DATE:

17-Feb-2014

Contact: Philip Bernstein, Ph.D. ITNCommunications@immunetolerance.org 240-235-6132 Immune Tolerance Network

WA, Seattle (February 17, 2014) 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 today 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 comprised 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.

###

View original post here:
Extensive renewal of the T cell repertoire following autologous stem cell transplant in MS

Deep TCR Sequencing Reveals Extensive Renewal of the T Cell Repertoire Following Autologous Stem Cell Transplant in …

By Stem Cell Treatment

Contact Information

Available for logged-in reporters only

Newswise WA, Seattle (February 17, 2014) 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 Networks (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 today in the Journal of Clinical Investigation (http://www.jci.org/articles/view/71691?key=b64763243f594bab6646) 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 comprised 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.

###

Originally posted here:
Deep TCR Sequencing Reveals Extensive Renewal of the T Cell Repertoire Following Autologous Stem Cell Transplant in ...

Rejuvenated Stem Cells Help Aging Muscles Heal

By Stem Cell Medicine

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.

A release from the university quotes Helen Blau PhD, the Donald and Delia B. Baxter Foundation Professor, as saying, "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. 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."

The release explains that 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 Stanford's Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, which was published online Feberuary 16th 2014 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. The researchers found that many muscle stem cells isolated from mice that were two years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells. Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage, Blau said. "Aging is a stochastic but cumulative process," Cosgrove said. The word stochastic mean a process involving chance or probability. Cosgorce added that the team has shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population, he said. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew."

The researchers found that, when transplanted back into the animal, the treated stem cells migrate to their natural niches and provide a long-lasting stem cell reserve to contribute to repeated demands for muscle repair. "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. In 2010, Blau's laboratory published a study in Science showing that muscle stem cells grown on soft hydrogel maintain their "stemness" in culture. In contrast, muscle stem cells grown on hard plastic tissue culture plates, the standard way to cultivate cells in the laboratory, quickly differentiate into more-specialized, but less therapeutically useful, muscle progenitor cells. The difference is likely due to the fact that soft hydrogel is more similar than rigid plastic to the muscle tissue environment in which the stem cells are naturally found. In the current study, the researchers found that targeting the p38 MAP kinase to induce the rapid expansion of the remaining functional stem cells from old mice required the soft hydrogel substrate. "The drug plus hydrogel boosts the small clones so that they undergo a burst of self-renewing divisions," Gilbert said. Thus, rejuvenation of the population is contingent on the synergy between biophysical and biochemical cues.

Finally, the researchers tested the ability of the rejuvenated old muscle stem cell population to repair muscle injury and restore strength in 2-year-old recipient mice. They teamed up with co-author Scott Delp, PhD, the James H. Clark Professor in the School of Engineering, who has designed a novel way to measure muscle strength in animals that had muscle injuries and then underwent the stem cell therapy. "We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice," Cosgrove said. "Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all." The researchers plan to continue their research to learn whether this technique could be used in humans. "If we could isolate the stem cells from an elderly person, expose them in culture to the proper conditions to rejuvenate them and transfer them back into a site of muscle injury, we may be able to use the person's own cells to aid recovery from trauma or to prevent localized muscle atrophy and weakness due to broken bones," Blau said. "This really opens a whole new avenue to enhance the repair of specific muscles in the elderly, especially after an injury. Our data pave the way for such a stem cell therapy."

### Other Stanford authors of the study include postdoctoral scholar Ermelinda Porpiglia, PhD; instructor Foteini Mourkioti, PhD; undergraduate student Steven Lee; senior research scientist Stephane Corbel, PhD; and medical resident Michael Llewellyn, MD, PhD. The research was supported by the National Institutes of Health (grants R25CA118681, K99AG042491, T32CA009151, K99AR061465, U01HL100397, U01HL099997, R01AG020961, R01HL096113 and R01AG009521), the California Institute for Regenerative Medicine and the Baxter Foundation.

View post:
Rejuvenated Stem Cells Help Aging Muscles Heal

SALK, STANFORD TEAM ON STEM CELL PROJECT

By Uncategorized

By Bradley J. Fikes U-T 12:01 a.m.Feb. 17, 2014

Instead of being shut out of a $40 million stem cell grant awarded to Stanford University, San Diego researchers will be major partners, say the scientists who lead the project.

Joseph Ecker of the Salk Institute and Michael Snyder of Stanford say that under an informal arrangement, they will jointly allocate money granted from the California Institute for Regenerative Medicine for a new center on stem cell genomics. CIRM is responsible for distributing $3 billion in state bond money to turn stem cell research into disease treatments.

Genomics, the study of the complete set of genes and DNA in an organism, is necessary to help understand how stem cells function. Stem cells contain virtually the same genes as adult cells but differ in which genes are turned on and off. The signals that cause stem cells to differentiate are not well understood.

By analyzing the genomes of stem cells, researchers expect to better understand how stem cells can produce more stem cells, and which genes are involved in directing stem cells down the path to becoming adult cells of interest, such as islet cells that make insulin, bone or retinal cells.

Last months decision had been characterized as a big win for Stanford, because the university had been awarded the grant over competing applications, including one from The Scripps Research Institute and San Diego DNA sequencing giant Illumina.

Ecker and Snyder said that belief is a misunderstanding, because their proposal is a cooperative venture involving extensive participation from San Diego biomedical scientists.

The leadership issue is confusing, because CIRM requires a single institute to be listed as the lead on funding proposals, even if the institutions are sharing leadership, Ecker said by email. In fact, Mike Snyder and I, by proxy Stanford and Salk, are equal partners. Responsibility for administration of the center will fall equally to Stanford and Salk researchers, as well as strategic steering and decision-making on what projects to pursue.

Besides Salk and Stanford, partners are UC San Diego, the Ludwig Institute for Cancer Research, the J. Craig Venter Institute, The Scripps Research Institute and UC Santa Cruz. The Howard Hughes Medical Institute also plays a role.

Ecker said the grant application was designed to allow equal participation by Salk and Stanford.

See the rest here:
SALK, STANFORD TEAM ON STEM CELL PROJECT

Researchers rejuvenate stem cell population from elderly mice, enabling muscle recovery

By Stem Cell Treatment

PUBLIC RELEASE DATE:

16-Feb-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. 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, 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," 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 Stanford's Baxter Laboratory for Stem Cell Biology, is the senior author of a paper describing the research, which will be 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.

The researchers found that many muscle stem cells isolated from mice that were 2 years old, equivalent to about 80 years of human life, exhibited elevated levels of activity in a biological cascade called the p38 MAP kinase pathway. This pathway impedes the proliferation of the stem cells and encourages them to instead become non-stem, muscle progenitor cells. As a result, although many of the old stem cells divide in a dish, the resulting colonies are very small and do not contain many stem cells.

Using a drug to block this p38 MAP kinase pathway in old stem cells (while also growing them on a specialized matrix called hydrogel) allowed them to divide rapidly in the laboratory and make a large number of potent new stem cells that can robustly repair muscle damage, Blau said.

"Aging is a stochastic but cumulative process," Cosgrove said. "We've now shown that muscle stem cells progressively lose their stem cell function during aging. This treatment does not turn the clock back on dysfunctional stem cells in the aged population. Rather, it stimulates stem cells from old muscle tissues that are still functional to begin dividing and self-renew."

Read more:
Researchers rejuvenate stem cell population from elderly mice, enabling muscle recovery

CU-Boulder stem cell research may point to new ways of mitigating muscle loss

By Stem Cell Medicine

PUBLIC RELEASE DATE:

16-Feb-2014

Contact: Bradley Olwin bradley.olwin@colorado.edu 303-492-6816 University of Colorado at Boulder

New findings on why skeletal muscle stem cells stop dividing and renewing muscle mass during aging points up a unique therapeutic opportunity for managing muscle-wasting conditions in humans, says a new University of Colorado Boulder study.

According to CU-Boulder Professor Bradley Olwin, the loss of skeletal muscle mass and function as we age can lead to sarcopenia, a debilitating muscle-wasting condition that generally hits the elderly hardest. The new study indicates that altering two particular cell-signaling pathways independently in aged mice enhances muscle stem cell renewal and improves muscle regeneration.

One cell-signaling pathway the team identified, known as p38 MAPK, appears to be a major player in making or breaking the skeletal muscle stem cell, or satellite cell, renewal process in adult mice, said Olwin of the molecular, cellular and developmental biology department. Hyperactivation of the p38 MAPK cell-signaling pathway inhibits the renewal of muscle stem cells in aged mice, perhaps because of cellular stress and inflammatory responses acquired during the aging process.

The researchers knew that obliterating the p38 MAPK pathway in the stem cells of adult mice would block the renewal of satellite cells, said Olwin. But when the team only partially shut down the activity in the cell-signaling pathway by using a specific chemical inhibitor, the adult satellite cells showed significant renewal, he said. "We showed that the level of signaling from this cellular pathway is very important to the renewal of the satellite cells in adult mice, which was a very big surprise," said Olwin.

A paper on the subject appeared online Feb. 16 in the journal Nature Medicine.

One reason the CU-Boulder study is important is that the results could lead to the use of low-dose inhibitors, perhaps anti-inflammatory compounds, to calm the activity in the p38 MAPK cell-signaling pathway in human muscle stem cells, said Olwin.

The CU-Boulder research team also identified a second cell-signaling pathway affecting skeletal muscle renewal a receptor known as the fibroblast growth factor receptor-1, or FGFR-1. The researchers showed when the FGFR-1 receptor protein was turned on in specially bred lab mice, the renewal of satellite cells increased significantly. "We still don't understand how that particular mechanism works," he said.

Read this article:
CU-Boulder stem cell research may point to new ways of mitigating muscle loss

Stem cell research forges ahead

By Stem Cell Medical Center

Written by: Cynthia Hernandez on October 7, 2010.

Despite opposition, use of embryos for testing continues

Why is the United States such a powerful country? Is it because we have a democracy?

Is it because our military capabilities exceed those of others? Is it because we have succeeded at prioritizing those policies that are most beneficial to the citizenry?

From civil rights movements to fighting a war on terror, the United States is at the forefront of advancement or is it?

It is safe to assume that most Americans support research and education. It is usually the case that anyone who is influential in some form or another has a significant educational background.

From lobbyists to police officers to the president of the United States, education plays a critical role in numerous professions.

One critical aspect of education is research. For example, political scientists research the political implications of differing democratic systems, biologists research DNA and English scholars research literary and poetic forms.

These topics will usually only interest and be of importance to people in similar fields.

But when research on a particular topic ignites controversy, it becomes a battle of academia versus personal beliefs.

Read the original here:
Stem cell research forges ahead

Salk, Stanford partner in genomics program

By Stem Cell Medical Center

Instead of being shut out of a $40 million stem cell grant awarded to Stanford University, San Diego researchers will be major partners, say the scientists who lead the project.

Joseph Ecker of the Salk Institute and Michael Snyder of Stanford say that under an informal arrangement, they will jointly allocate money granted from the California Institute for Regenerative Medicine for a new center on stem cell genomics. CIRM is responsible for distributing $3 billion in state bond money to turn stem cell research into disease treatments.

Joseph Ecker, a Salk Institute researcher and co-principal investigator of the new center for stem cell genomics created with a $40 million grant from the California Institute for Regenerative Medicine. / Salk Institute

Genomics, the study of the complete set of genes and DNA in an organism, is necessary to help understand how stem cells function. Stem cells contain virtually the same genes as adult cells but differ in which genes are turned on and off. The signals that cause stem cells to differentiate are not well understood.

By analyzing the genomes of stem cells, researchers expect to better understand how stem cells can produce more stem cells, and which genes are involved in directing stem cells down the path to becoming adult cells of interest, such as islet cells that make insulin, bone or retinal cells.

Last months decision had been characterized as a big win for Stanford, because the university had been awarded the grant over competing applications, including one from The Scripps Research Institute and San Diego DNA sequencing giant Illumina.

Ecker and Snyder said that belief is a misunderstanding, because their proposal is a cooperative venture involving extensive participation from San Diego biomedical scientists.

Michael Snyder, a Stanford University researcher and co-principal investigator of the new center for stem cell genomics created with a $40 million grant from the California Institute for Regenerative Medicine. / Stanford University

The leadership issue is confusing, because CIRM requires a single institute to be listed as the lead on funding proposals, even if the institutions are sharing leadership, Ecker said by email. In fact, Mike Snyder and I, by proxy Stanford and Salk, are equal partners. Responsibility for administration of the center will fall equally to Stanford and Salk researchers, as well as strategic steering and decision-making on what projects to pursue.

Besides Salk and Stanford, partners are UC San Diego, the Ludwig Institute for Cancer Research, the J. Craig Venter Institute, The Scripps Research Institute and UC Santa Cruz. The Howard Hughes Medical Institute also plays a role.

See more here:
Salk, Stanford partner in genomics program

Stem Cell Therapy | Advanced Orthopedics | Regenerative …

By Stem Cell Medicine

It's been nothing but 100% improvement.It just continues to get better.Ive been avoiding doing stairways and I have to be real careful climbing in and out of equipment. I find myself being a lot more relaxed, not having the problems, not having the pain. I don't have the swelling in my knees that I used to have and it hasnt been waking me up at night. View my video testimonial here My name is Susan and Im 62 year old I just finished having my second PRP treatment and Im very, very happy with the results I can do all kinds of things I wasn't able to do beforeI believe my knee will continue to get better as the cartilage grows. Thank you! View my video testimonial here

Many thanks to the Stem MD team for giving me the use of my hands back, pain free! Professional, courteous and compassionate, describes this team of caring people. To anyone considering this procedure, I say you will be amazed and thankful at the results.

Lenita Brewer Ansonia, Ohio

Thank you for giving my life and health back. The PRP treatment worked wonders and helped alleviate the pain. I highly recommend the anti-inflammatory diet, Dr. Purita suggested. My body noticed the difference and I lost 35 pounds. I can finally be active again!

Jennica Califf Coconut Creek, Florida

I thought there was no hope for my chronic back pain. I am so thankful I found out about Dr. Purita and stem cells. I have had back pain for over 5 years, debilitating me to do everyday things. Today my pain has gone down 50%. I tell all my friends and family and wish everyone knew about this wonderful treatment. Thank you so much Dr. Purita

It has been 3 months since my mothers procedure to her knees. Now, my mom climbs into the van without any help, before we had to pull her up and assist her. She does not take painkillers anymore, even her recurring bladder infection and Diabetes is well controlled. All my friends and colleagues are super amazed every time I show them a video of my mom dancing. Thank you so much what you have done for my mom it is truly wonderful and I am forever indebted to you.

Malou Aragon-De Veyra Philippines

I came to Dr. Purita on the advice of a friend when I expressed trepidations about cortisone shots or the possibility no matter how remote of a joint replacement. I was a wrestler in high school and college, and this had done no good for my kneed as I aged. I had no expectations, only hope that somehow my knees could be made less fragile by the stem cell therapy my friend described. I had gotten to the point where any down stairs journey or stepping down off a van or public bus was excruciating, to the point that I usually made an exclamation that wasn't fit for public utterance every time I stepped off a bus or a van. My expectations were neutral at best. I had no idea as to how this stem cell therapy would impact my general health whatsoever. I can say without hesitation that the results have been beyond what I could have hoped. My knees are now cooperative to the point that sometimes I take the stairs down just because I can. I have resumed walking the stairs up and down at work, and I can say that I really don't think about anything I want to do where my kneed are involved. I am not quite where I was when I was 20, but 35 is a real thought, my flexibility and agility are restored to a level I could not have imagined. As an additional part of the procedure Dr. Purita also injected stem cell into my left hand, which has been diagnosed with some arthritis. The results are less instantaneously spectacular, but the had continues to improve. I no longer sit in my office while my hand burns with joint pain, my movement and most of my strength are improving daily, and I have a feeling that within a month or so I will have the same level of improvement I have experiences with my knees. Many thanks to the friend who recommended the trip to Dr. Purita's office, and to Dr. Purita and his staff who have put thoughts of joint replacement and the mad merry-go-round of cortisone shots far in the past for me.

Mark Burns Hypoluxo, Florida

See the rest here:
Stem Cell Therapy | Advanced Orthopedics | Regenerative ...

→←