PUBLIC RELEASE DATE:

7-Sep-2014

Contact: Paddy Moore padmoore@ohri.ca 613-737-8899 x73687 Ottawa Hospital Research Institute

Ottawa, Canada (September 7, 2014) As we age, stem cells throughout our bodies gradually lose their capacity to repair damage, even from normal wear and tear. Researchers from the Ottawa Hospital Research Institute and University of Ottawa have discovered the reason why this decline occurs in our skeletal muscle. Their findings were published online today in the influential journal Nature Medicine.

A team led by Dr. Michael Rudnicki, senior scientist at the Ottawa Hospital Research Institute and professor of medicine at the University of Ottawa, found that as muscle stem cells age, their reduced function is a result of a progressive increase in the activation of a specific signalling pathway. Such pathways transmit information to a cell from the surrounding tissue. The particular culprit identified by Dr. Rudnicki and his team is called the JAK/STAT signalling pathway.

"What's really exciting to our team is that when we used specific drugs to inhibit the JAK/STAT pathway, the muscle stem cells in old animals behaved the same as those found in young animals," said Dr. Michael Rudnicki, a world leader in muscle stem cell research. "These inhibitors increased the older animals' ability to repair injured muscle and to build new tissue."

What's happening is that our skeletal muscle stem cells are not being instructed to maintain their population. As we get older, the activity of the JAK/STAT pathway shoots up and this changes how muscle stem cells divide. To maintain a population of these stem cells, which are called satellite cells, some have to stay as stem cells when they divide. With increased activity of the JAK/STAT pathway, fewer divide to produce two satellite cells (symmetric division) and more commit to cells that eventually become muscle fibre. This reduces the population of these regenerating satellite cells, which results in a reduced capacity to repair and rebuild muscle tissue.

While this discovery is still at early stages, Dr. Rudnicki's team is exploring the therapeutic possibilities of drugs to treat muscle-wasting diseases such as muscular dystrophy. The drugs used in this study are commonly used for chemotherapy, so Dr. Rudnicki is now looking for less toxic molecules that would have the same effect.

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The full article titled "Inhibition of JAK/STAT signaling stimulates adult satellite cell function" was published online September 7, 2014, by Nature Medicine.

Read more from the original source:
Why age reduces our stem cells' ability to repair muscle

44 minutes ago by Terry Devitt When blank slate stem cells are exposed to a soft as opposed to a hard surface on which to grow, they begin to transform themselves into neurons, the large, complex cells of the central nervous system. Absent any soluble factors to direct cell differentiation, surface matters, according to new research from the lab of University of Wisconsin-Madison chemist and biochemist Laura Kiessling. Credit: Kiessling Lab/UW-Madison

Figuring out how blank slate stem cells decide which kind of cell they want to be when they grow upa muscle cell, a bone cell, a neuronhas been no small task for science.

Human pluripotent stem cells, the undifferentiated cells that have the potential to become any of the 220 types of cells in the body, are influenced in the lab dish by the cocktail of chemical factors and proteins upon which they are grown and nurtured. Depending on the combination of factors used in a culture, the cells can be coaxed to become specific types of cells.

Now, in a new study published today, Sept. 8, in the Proceedings of the National Academy of Sciences, a team of researchers from the University of Wisconsin-Madison has added a new wrinkle to the cell differentiation equation, showing that the stiffness of the surfaces on which stem cells are grown can exert a profound influence on cell fate.

"To derive lineages, people use soluble growth factors to get the cells to differentiate," explains Laura Kiessling, a UW-Madison professor of chemistry and biochemistry and stem cell expert.

Past work, she notes, hinted that the qualities of the surface on which a cell lands could exert an influence on cell fate, but the idea was never fully explored in the context of human pluripotent stem cell differentiation.

In the lab, stem cells are grown in plastic dishes coated with a gel that contains as many as 1,800 different proteins. Different factors can be introduced to obtain certain types of cells. But even in the absence of introduced chemical or protein cues, the cells are always working to differentiatebut in seemingly random, undirected ways.

The Wisconsin group, directed by Kiessling and led by chemistry graduate student Samira Musah, decided to test the idea that the hardness of a surface can make a difference. After all, in a living body, cells seek different niches with different qualities and transform themselves accordingly.

"Many cell types grow on a surface. If a cell is near bone, the environment has certain features," says Kiessling, whose groupcollaborating with UW-Madison colleagues Sean Palecek, Qiang Chang and William Murphyhas been working to produce precise, chemically defined surfaces on which to grow stem cells. "A cell will react differently if it lands near soft tissue like the brain."

To fully explore the idea that surface matters to a stem cell, Kiessling's group created gels of different hardness to mimic muscle, liver and brain tissues. The study sought to test whether the surface alone, absent any added soluble factors to influence cell fate decisions, can have an effect on differentiation.

More here:
In directing stem cells, study shows context matters

A new study has revealed the reason behind why when people get older; the stem cells in their bodies start to lose the ability to repair even the normal muscle damage.

Researchers from the Ottawa Hospital Research Institute and University of Ottawa have discovered as muscle stem cells age, their reduced function was a result of a progressive increase in the activation of a specific signalling pathway. Such pathways transmit information to a cell from the surrounding tissue. The particular culprit identified was called the JAK/STAT signalling pathway.

What's happening was that the skeletal muscle stem cells are not being instructed to maintain their population. As peopleget older, the activity of the JAK/STAT pathway shoots up and this changes how muscle stem cells divide. To maintain a population of these stem cells, which are called satellite cells, some have to stay as stem cells when they divide.

With increased activity of the JAK/STAT pathway, fewer divide to produce two satellite cells (symmetric division) and more commit to cells that eventually become muscle fibre. This reduces the population of these regenerating satellite cells, which results in a reduced capacity to repair and rebuild muscle tissue.

Dr. Michael Rudnicki, senior scientist at the Ottawa Hospital Research Institute and his team was now exploring the therapeutic possibilities of drugs to treat muscle-wasting diseases such as muscular dystrophy.

The study is published in the influential journal Nature Medicine.

(Posted on 08-09-2014)

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Why stem cells lose capacity to repair damaged muscle with aging revealed

Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have developed a novel technique to promote tissue repair in damaged muscles. The technique also creates a sustainable pool of muscle stem cells needed to support multiple rounds of muscle repair. The study, published September 7 in Nature Medicine, provides promise for a new therapeutic approach to treating the millions of people suffering from muscle diseases, including those with muscular dystrophies and muscle wasting associated with cancer and aging.

There are two important processes that need to happen to maintain skeletal-muscle health. First, when muscle is damaged by injury or degenerative disease such as muscular dystrophy, muscle stem cells -- or satellite cells -- need to differentiate into mature muscle cells to repair injured muscles. Second, the pool of satellite cells needs to be replenished so there is a supply to repair muscle in case of future injuries. In the case of muscular dystrophy, the chronic cycles of muscle regeneration and degeneration that involve satellite-cell activation exhaust the muscle stem-cell pool to the point of no return.

"Our study found that by introducing an inhibitor of the STAT3 protein in repeated cycles, we could alternately replenish the pool of satellite cells and promote their differentiation into muscle fibers," said Alessandra Sacco, Ph.D., assistant professor in the Development, Aging, and Regeneration Program at Sanford-Burnham. "Our results are important because the process works in mice and in human muscle cells."

"Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans," added Sacco.

"These findings are very encouraging. Currently, there is no cure to stop or reverse any form of muscle-wasting disorders -- only medication and therapy that can slow the process," said Vittorio Sartorelli, M.D., chief of the Laboratory of Muscle Stem Cells and Gene Regulation and deputy scientific director at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). "A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough."

Revealing the mechanism of STAT3

STAT3 (signal transducer and activator of transcription 3) is a protein that activates the transcription of genes in response to IL-6, a signaling protein released by cells in response to injury and inflammation. Prior to the study, scientists knew that STAT3 played a complex role in skeletal muscle, promoting tissue repair in some instances and hindering it in others. But the precise mechanism of how STAT3 worked was a mystery.

The research team first used normally aged mice and mice models of a form of muscular dystrophy that resembles the human disease to see what would happen if they were given a drug to inhibit STAT3. They found that the inhibitor initially promoted satellite-cell replication, followed by differentiation of the satellite cells into muscle fibers. When they injected the STAT3 inhibitor every seven days for 28 days, they found an overall improvement in skeletal-muscle repair, and an increase in the size of muscle fibers.

"We were pleased to find that we achieved similar results when we performed the experiments in human muscle cells," said Sacco. "We have discovered that by timing the inhibition of STAT3 -- like an "on/off" light switch -- we can transiently expand the satellite-cell population followed by their differentiation into mature muscle cells."

Story Source:

Original post:
Researchers discover key to making new muscles

As we age, stem cells throughout our bodies gradually lose their capacity to repair damage, even from normal wear and tear. Researchers from the Ottawa Hospital Research Institute and University of Ottawa have discovered the reason why this decline occurs in our skeletal muscle. Their findings were published online in the influential journal Nature Medicine.

A team led by Dr. Michael Rudnicki, senior scientist at the Ottawa Hospital Research Institute and professor of medicine at the University of Ottawa, found that as muscle stem cells age, their reduced function is a result of a progressive increase in the activation of a specific signalling pathway. Such pathways transmit information to a cell from the surrounding tissue. The particular culprit identified by Dr. Rudnicki and his team is called the JAK/STAT signalling pathway.

"What's really exciting to our team is that when we used specific drugs to inhibit the JAK/STAT pathway, the muscle stem cells in old animals behaved the same as those found in young animals," said Dr. Michael Rudnicki, a world leader in muscle stem cell research. "These inhibitors increased the older animals' ability to repair injured muscle and to build new tissue."

What's happening is that our skeletal muscle stem cells are not being instructed to maintain their population. As we get older, the activity of the JAK/STAT pathway shoots up and this changes how muscle stem cells divide. To maintain a population of these stem cells, which are called satellite cells, some have to stay as stem cells when they divide. With increased activity of the JAK/STAT pathway, fewer divide to produce two satellite cells (symmetric division) and more commit to cells that eventually become muscle fibre. This reduces the population of these regenerating satellite cells, which results in a reduced capacity to repair and rebuild muscle tissue.

While this discovery is still at early stages, Dr. Rudnicki's team is exploring the therapeutic possibilities of drugs to treat muscle-wasting diseases such as muscular dystrophy. The drugs used in this study are commonly used for chemotherapy, so Dr. Rudnicki is now looking for less toxic molecules that would have the same effect.

Story Source:

The above story is based on materials provided by Ottawa Hospital Research Institute. Note: Materials may be edited for content and length.

See the original post:
Why age reduces stem cells' ability to repair muscle