Rejuvenated Stem Cells Help Aging Muscles Heal

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.

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Rejuvenated Stem Cells Help Aging Muscles Heal

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

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.

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

Stem Cell Therapy | Advanced Orthopedics | Regenerative …

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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.

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Stem Cells -Medical News Today

knowledge center home stem cell research all about stem cells what are stem cells?

Stem cells are a class of undifferentiated cells that are able to differentiate into specialized cell types. Commonly, stem cells come from two main sources:

Both types are generally characterized by their potency, or potential to differentiate into different cell types (such as skin, muscle, bone, etc.).

Adult or somatic stem cells exist throughout the body after embryonic development and are found inside of different types of tissue. These stem cells have been found in tissues such as the brain, bone marrow, blood, blood vessels, skeletal muscles, skin, and the liver. They remain in a quiescent or non-dividing state for years until activated by disease or tissue injury.

Adult stem cells can divide or self-renew indefinitely, enabling them to generate a range of cell types from the originating organ or even regenerate the entire original organ. It is generally thought that adult stem cells are limited in their ability to differentiate based on their tissue of origin, but there is some evidence to suggest that they can differentiate to become other cell types.

Embryonic stem cells are derived from a four- or five-day-old human embryo that is in the blastocyst phase of development. The embryos are usually extras that have been created in IVF (in vitro fertilization) clinics where several eggs are fertilized in a test tube, but only one is implanted into a woman.

Sexual reproduction begins when a male's sperm fertilizes a female's ovum (egg) to form a single cell called a zygote. The single zygote cell then begins a series of divisions, forming 2, 4, 8, 16 cells, etc. After four to six days - before implantation in the uterus - this mass of cells is called a blastocyst. The blastocyst consists of an inner cell mass (embryoblast) and an outer cell mass (trophoblast). The outer cell mass becomes part of the placenta, and the inner cell mass is the group of cells that will differentiate to become all the structures of an adult organism. This latter mass is the source of embryonic stem cells - totipotent cells (cells with total potential to develop into any cell in the body).

In a normal pregnancy, the blastocyst stage continues until implantation of the embryo in the uterus, at which point the embryo is referred to as a fetus. This usually occurs by the end of the 10th week of gestation after all major organs of the body have been created.

However, when extracting embryonic stem cells, the blastocyst stage signals when to isolate stem cells by placing the "inner cell mass" of the blastocyst into a culture dish containing a nutrient-rich broth. Lacking the necessary stimulation to differentiate, they begin to divide and replicate while maintaining their ability to become any cell type in the human body. Eventually, these undifferentiated cells can be stimulated to create specialized cells.

Stem cells are either extracted from adult tissue or from a dividing zygote in a culture dish. Once extracted, scientists place the cells in a controlled culture that prohibits them from further specializing or differentiating but usually allows them to divide and replicate. The process of growing large numbers of embryonic stem cells has been easier than growing large numbers of adult stem cells, but progress is being made for both cell types.

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Stem Cells -Medical News Today

Director of Womens Guild Lung Institute Awarded Stem …

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Newswise LOS ANGELES (Feb. 6, 2014) A Cedars-Sinai research team led by Paul W. Noble, MD, chair of the Department of Medicine and director of the Women's Guild Lung Institute, has been awarded $628,816 by Californias stem cell agency to develop a treatment for idiopathic pulmonary fibrosis, a deadly disease that destroys the lungs and damages other vital organs.

The illness, which has no cure and few effective treatments, thickens and hardens lung tissue, leaving the organs badly scarred. Patients with idiopathic pulmonary fibrosis have great difficulty breathing and the chronic reduction in oxygen damages vital organs. The cause of the disease is not clearly understood and many people live only three to five years after diagnosis.

Lung fibrosis occurs when the lung is unable to repair itself properly after injury or infection, said Noble. Some people are more susceptible to developing fibrosis, and we currently dont understand why the normal repair and renewal of lung cells stops occurring in these patients.

The two-year study will build upon preliminary research completed at Cedars-Sinai by Noble and physician researcher Dianhua Jiang, MD, PhD. They uncovered important clues to the precise way normal lung stem cell repair occurs and how a cure might be developed.

Currently, there is no therapy for idiopathic pulmonary fibrosis approved by the Food and Drug Administration. The only effective therapy is lung transplantation, which we do here at Cedars-Sinai, said Noble. But if successful, our research will result in a completely novel approach to the treatment of lung diseases, allowing for the renewal and repair of the patients cells.

This phase of Nobles research will involve the study of laboratory mice and human tissue to further identify the exact mechanisms necessary for stem cells to repair damage to the lungs.

Funding these awards highlights our commitment to advancing the field with the most cutting-edge approaches and to help deepen our understanding of every aspect of stem cells, to help us find new treatments, and even cures for the deadliest diseases, said Jonathan Thomas, PhD, JD, chair of the governing Board of the California Institute for Regenerative Medicine.

This award is a reflection of the highest peer recognition of Dr. Nobles scholarly efforts to discover novel approaches for understanding pathogenesis and new therapies for lung disorders, said Shlomo Melmed, MD, senior vice president for academic affairs, dean of the medical faculty and the Helene A. and Philip E. Hixon Chair in Investigative Medicine.

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Director of Womens Guild Lung Institute Awarded Stem ...

Histones may hold the key to the generation of totipotent stem cells

1 hour ago This image shows iPS cells (green) generated using histone variants TH2A and TH2B and two Yamanaka factors (Oct3/4 and Klf4). Credit: RIKEN

One major challenge in stem cell research has been to reprogram differentiated cells to a totipotent state. Researchers from RIKEN in Japan have identified a duo of histone proteins that dramatically enhance the generation of induced pluripotent stem cells (iPS cells) and may be the key to generating induced totipotent stem cells.

Differentiated cells can be coaxed into returning to a stem-like pluripotent state either by artificially inducing the expression of four factors called the Yamanaka factors, or as recently shown by shocking them with sublethal stress, such as low pH or pressure. However, attempts to create totipotent stem cells capable of giving rise to a fully formed organism, from differentiated cells, have failed.

The study, published today in the journal Cell Stem Cell and led by Dr. Shunsuke Ishii from RIKEN, sought to identify the molecule in the mammalian oocyte that induces the complete reprograming of the genome leading to the generation of totipotent embryonic stem cells. This is the mechanism underlying normal fertilization, as well as the cloning technique called Somatic-Cell Nuclear Transfer (SCNT).

SCNT has been used successfully to clone various species of mammals, but the technique has serious limitations and its use on human cells has been controversial for ethical reasons.

Ishii and his team chose to focus on two histone variants named TH2A and TH2B, known to be specific to the testes where they bind tightly to DNA and affect gene expression.

The study demonstrates that, when added to the Yamanaka cocktail to reprogram mouse fibroblasts, the duo TH2A/TH2B increases the efficiency of iPSC cell generation about twentyfold and the speed of the process two- to threefold. And TH2A and TH2B function as substitutes for two of the Yamanaka factors (Sox2 and c-Myc).

By creating knockout mice lacking both proteins, the researchers show that TH2A and TH2B function as a pair, are highly expressed in oocytes and fertilized eggs and are needed for the development of the embryo after fertilization, although their levels decrease as the embryo grows.

In the early embryo, TH2A and TH2B bind to DNA and induce an open chromatin structure in the paternal genome, thereby contributing to its activation after fertilization.

These results indicate that TH2A/TH2B might induce reprogramming by regulating a different set of genes than the Yamanaka factors, and that these genes are involved in the generation of totipotent cells in oocyte-based reprogramming as seen in SCNT.

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Stem Cell Research at the 2014 NJ Symposium on Biomaterials Science

Piscataway, NJ (PRWEB) February 06, 2014

Mahendra Rao, MD, PhD, the Director of the Center for Regenerative Medicine (CRM) at the National Institutes of Health (NIH) has agreed to be a keynote speaker at the 12th edition of the New Jersey Symposium Biomaterials Science. Dr. Rao is internationally renowned for his research involving human embryonic stem cells and other somatic stem cells. He has worked in the stem cell field for more than 20 years with stints in academia, government and regulatory affairs, and industry. Dr. Rao will address the role of biomaterials for stem cell therapies in a session devoted to scientific breakthroughs leading to clinical applications.

Along with Dr. Rao, the 12th edition of the New Jersey Symposium on Biomaterials Science will feature a roster of presentations by 30 leading scientists, many with global reputations for their work in academia and industry in the areas of biomaterials, bioengineering and clinical practice.

Detailed information about the symposium and registration links will be found at http://www.njbiomaterials.org/biomaterials-symposia.htm.

The New Jersey Center for Biomaterials (NJCBM) was founded in 1997. Based at Rutgers, the State University of New Jersey, the center spans academia, industry and government. Staffed by biomaterial scientists, the Center works to improve health care and quality of life by developing advanced biomedical products for tissue repair and replacement as well as the delivery of pharmaceutical agents. The Centers technologies have been translated into clinical and pre-clinical products including surgical meshes, cardiovascular stents, bone regeneration scaffolds, and ocular drug delivery systems.

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Louli Kourkounakis (732) 445 0488 ext. 40001 symposium(at)dls(dot)rutgers(dot)edu

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Stem Cell Research at the 2014 NJ Symposium on Biomaterials Science

Extraordinary stem cell method tested in human tissue

(Image: Charles Vacanti and Koji Kojima, Harvard Medical School)

Talk about speedy work. Hot on the heels of the news that simply dipping adult mouse cells in acid could turn them into cells with the potential to turn into any cell in the body, it appears that the same thing may have been done using human cells.

The picture above, given to New Scientist by Charles Vacanti at Harvard Medical School, is said to be images of the first human "STAP cell" experiments.

Last week, the scientific world was bowled over by a study in Nature showing that an acidic environment turned adult mouse cells into "totipotent" stem cells which can turn into any cell in the body or placenta. The researchers called these new totipotent cells stimulus-triggered acquisition of pluripotency (STAP) cells.

"If they can do this in human cells, it changes everything," Rob Lanza of Advanced Cell Technologies in Marlborough, Massachusetts, said at the time. The technique promises cheaper, quicker and potentially more flexible cells for regenerative medicine, cancer therapy and cloning.

Now, Vacanti and his colleagues say they have taken human fibroblast cells and tested several environmental stressors on them in an attempt to recreate human STAP cells. He won't reveal what type of stressors were applied but he says the resulting cells appears similar in form to the mouse STAP cells. His team is in the process of testing to see just how stem-cell-like these cells are.

Vacanti says that the human cells took about a week to resemble STAP cells, and formed spherical clusters just like their mouse counterparts. Using a similar experimental set-up with green monkey (Chlorocebus sabaeus) cells, Vacanti says the resulting cells are behaving slightly differently. He says that may be due to the fact that the researchers used slightly different techniques. Both Vacanti and his Harvard colleague Koji Kojima emphasise that these results are only preliminary and much further analysis and validation is required.

"Even if these are STAP cells they may not necessarily have the same potential as mouse ones they may not have the totipotency which is one of the most interesting features of the mouse cells," says Sally Cowley, head of the James Martin Stem Cell Facility at the University of Oxford.

Pluripotent cells, such as embryonic stem cells, can form any cell in an embryo but not a placenta. Totipotent cells, however, can form any cell in an embryo and a placenta meaning they have the potential to create life. The only cells known to be naturally totipotent are in embryos that have only undergone the first couple of cell divisions immediately after fertilisation.

Research using totipotent cells would have to be under very strict regulatory surveillance, says Cowley. "It would actually be ideal if the human cells could be pluripotent and not totipotent it would make everyone's life a lot easier."

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Extraordinary stem cell method tested in human tissue

New protein breakthrough brings leukemia cure closer to reality

Washington, Feb 03 : A team of researchers has identified a protein critical to hematopoietic stem cell function and blood formation.

The finding has potential as a new target for treating leukemia because cancer stem cells rely upon the same protein to regulate and sustain their growth.

Principal investigator Tannishtha Reya from the University of California, San Diego School of Medicine, along with her colleagues found that a protein called Lis1 fundamentally regulates asymmetric division of hematopoietic stem cells, assuring that the stem cells correctly differentiate to provide an adequate, sustained supply of new blood cells.

Asymmetric division occurs when a stem cell divides into two daughter cells of unequal inheritance: One daughter differentiates into a permanently specialized cell type while the other remains undifferentiated and capable of further divisions.

"This process is very important for the proper generation of all the cells needed for the development and function of many normal tissues," Reya said. When cells divide, Lis1 controls orientation of the mitotic spindle, an apparatus of subcellular fibers that segregates chromosomes during cell division.

When researchers deleted Lis1 from mouse hematopoietic stem cells, differentiation was radically altered. Asymmetric division increased and accelerated differentiation, resulting in an oversupply of specialized cells and an ever-diminishing reserve of undifferentiated stem cells, which eventually resulted in a bloodless mouse.

Reya said that they found that a large part of the defect in blood formation was due to a failure of stem cells to expand. Instead of undergoing symmetric divisions to generate two stem cell daughters, they predominantly underwent asymmetric division to generate more specialized cells.

As a result, the mice were unable to generate enough stem cells to sustain blood cell production, the researcher said.

Reya said the findings shed new light on the fundamental regulators of cell growth both in normal development and in cancer.

The study was published in the journal Nature Genetics.

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New protein breakthrough brings leukemia cure closer to reality

Stem cell researchers heralding major scientific discovery

January 29, 2014 - 17:55 AMT

PanARMENIAN.Net - Stem cell researchers are heralding a "major scientific discovery", with the potential to start a new age of personalized medicine, BBC News reports.

Scientists in Japan showed stem cells can now be made quickly just by dipping blood cells into acid.

Stem cells can transform into any tissue and are already being trialled for healing the eye, heart and brain.

The latest development, published in the journal Nature, could make the technology cheaper, faster and safer, according to the BBC.

The human body is built of cells with a specific role - nerve cells, liver cells, muscle cells - and that role is fixed. However, stem cells can become any other type of cell, and they have become a major field of research in medicine for their potential to regenerate the body.

Embryos are one, ethically charged, source of stem cells. Nobel prize winning research also showed that skin cells could be "genetically reprogrammed" to become stem cells (termed induced pluripotent stem cells).

Now a study shows that shocking blood cells with acid could also trigger the transformation into stem cells - this time termed STAP (stimulus-triggered acquisition of pluripotency) cells.

Dr Haruko Obokata, from the Riken Centre for Developmental Biology in Japan, said she was "really surprised" that cells could respond to their environment in this way.

She added: "It's exciting to think about the new possibilities these findings offer us, not only in regenerative medicine, but cancer as well."

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Stem cell researchers heralding major scientific discovery