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."

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

PUBLIC RELEASE DATE:

13-Feb-2014

Contact: Joseph Caputo joseph_caputo@harvard.edu 617-496-1491 Harvard University

Harvard stem cell scientists have a new theory for how stem cells decide whether to become liver or pancreatic cells during development. A cell's fate, the researchers found, is determined by the nearby presence of prostaglandin E2, a messenger molecule best known for its role in inflammation and pain. The discovery, published in the journal Developmental Cell, could potentially make liver and pancreas cells easier to generate both in the lab and for future cell therapies.

Wolfram Goessling, MD, PhD, and Trista North, PhD, both principal faculty members of the Harvard Stem Cell Institute (HSCI), identified a gradient of prostaglandin E2 in the region of zebrafish embryos where stem cells differentiate into the internal organs. Experiments conducted by postdoctoral fellow Sahar Nissim, MD, PhD, in the Goessling lab showed how liver-or-pancreas-fated stem cells have specific receptors on their membranes to detect the amount of prostaglandin E2 hormone present and coerce the cell into differentiating into a specific organ type.

"Cells that see more prostaglandin become liver and the cells that see less prostaglandin become pancreas," said Goessling, a Harvard Medical School Assistant Professor of Medicine at Brigham and Women's Hospital and Dana-Farber Cancer Institute. "This is the first time that prostaglandin is being reported as a factor that can lead this fate switch and essentially instruct what kind of identity a cell is going to be."

The researchers next collaborated with the laboratory of HSCI Affiliated Faculty member Richard Maas, MD, PhD, Director of the Genetics Division at Brigham and Women's Hospital, to see whether prostaglandin E2 has a similar function in mammals. Richard Sherwood, PhD, a former graduate student of HSCI Co-director Doug Melton, was successfully able to instruct mouse stem cells to become either liver or pancreas cells by exposing them to different amounts of the hormone. Other experiments showed that prostaglandin E2 could also enhance liver growth and regeneration of liver cells.

Goessling and his research partner North, a Harvard Medical School Assistant Professor of Pathology at Beth Israel Deaconess Hospital, first became intrigued by prostaglandin E2 in 2005, as postdoctoral fellows in the lab of HSCI Executive Committee Chair Leonard Zon, MD. It caught their attention during a chemical screen exposing 2,500 known drugs to zebrafish embryos to find any that could amplify blood stem cell populations. Prostaglandin E2 was the most successful hit the first molecule discovered in any system to have such an effectand recently successfully completed Phase 1b clinical trials as a therapeutic to improve cord blood transplants.

"Prostaglandin might be a master regulator of cell growth in different organs," Goessling said. "It's used in cord blood, as we have shown, it works in the liver, and who knows what other organs might be affected by it."

With evidence of how prostaglandin E2 works in the liver, the researchers next want to calibrate how it can be used in the laboratory to instruct induced pluripotent stem cellsmature cells that have been reprogrammed into a stem-like stateto become liver or pancreas cells. The scientists predict that such a protocol could benefit patients who need liver cells for transplantation or who have had organ injury.

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Harvard scientists find cell fate switch that decides liver, or pancreas?

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.

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Salk, Stanford equal partners in stem cell genomics program