Monthly Archives: February 2014

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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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

Claims by a Japanese research team that it made pluripotent stem cells simply by exposing normal mouse cells to acid baths and other stresses are now being investigated for "alleged irregulaties," according to an online article Monday in the journal Nature.

Mouse cells exposed to an acidic environment turned into embryonic-like "STAP" cells. These were used to generate an entire fetus. / Haruko Obokata

The study itself was published in Nature on Jan. 29. It gained widespread acclaim, but a number of scientists expressed doubts about the STAP cells on second thought. UC Davis stem cell researcher Paul Knoepfler gave his reasons for skepticism in a Feb. 6 blog post. Among his reasons: Evolution should have selected against such a mechanism, because cellular stress is a common part of life, and pluripotent stem cells produce tumors.

At the very least, researchers who have tried to replicate the findings aren't having an easy time doing so, according to an unscientific poll Knoepfler is running. The trend has turned from mostly positive to evenly split, Knoepfler reported in the second week of polling.

"Its also notable that respondents from Japan have shifted the most in opinion. In week 1 they were disproportionately positive, while in week 2 they became disproportionately negative," Knoepfler wrote.

Jeanne Loring, the TSRI stem cell researcher who I interviewed when the discovery was first announced, told me earlier this month that her lab, "along with everyone else in the universe," was trying to replicate the results.

"What I told my lab was, go ahead and do it; don't tell me about it until you have results, and don't let it interfere with the rest of your work," Loring said.

Life scientists from other fields weighed in on Twitter with their skepticism.

"Acid bath makes stem cells??? If it looks too good to be true, it probably is," wrote tart-tongued evolutionary biologist Dan Graur, who notably applied acid to claims by the ENCODE project (in its press release) that 80 percent of the human genome is functional.

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Acid test for STAP cells

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

TOKYO: A Japanese research institute on Tuesday said itwas probing its own study that promised a 'game changer' way to create stem cells, a feat hailed as revolutionary for the fast-developing field.

The findings, published by Japanese researcher Haruko Obokata and American partners in a January edition of the British journal Nature, outlined a simple and low-tech approach in the quest to grow transplant tissue in the lab.

The national institute Riken said Tuesday it had started an investigation over "questions" about the methodology and input data of the study, appointing several in-house and outside experts to pore over the revolutionary report. Obokata works for the institute.

At issue are allegations that the researchers used erroneous image data for the high-profile article, local media reported.

"The experts have already started hearings for the researchers involved in the articles," an institute spokesman said Tuesday, but declined to give further details.

For the moment, the institute is standing by the results -- a spokesman insisted the "findings themselves are unassailable."

Stem cells are primitive cells that, as they grow, differentiate into the various specialised cells that make up the different organs -- the brain, the heart, kidney and so on.

The goal is to create stem cells in the lab and nudge them to grow into these differentiated cells, thus replenishing organs damaged by disease or accident.

The researchers' groundbreaking findings said that white blood cells in newborn mice were returned to a versatile state by incubating them in a solution with high acidity for 25 minutes, followed by a five minute spin in a centrifuge and a seven-day spell of immersion in a growth culture.

Called stimulus-triggered acquisition of pluripotency (STAP) cells, the innovation breaks new ground.

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'Game changing' Japan stem-cell study questioned