Another Method of Restoring Activity in Old Muscle Stem Cells

Stem cell activity progressively declines with age, leading to lapsed tissue maintenance and increasing dysfunction and frailty. The role of stem cells is after all to replenish tissues, to provide a supply of fresh cells to replace those lost by the normal turnover, as well as issuing signals that spur other cell types into repair and regenerative efforts. Why does stem cell activity diminish? It is most likely an evolved reaction to rising levels of cellular damage, and serves to reduce the risk of cancer: our long life span in comparison to other primates is a balancing act between death by cancer on the one hand and death by tissue failure on the other. This in turn may have came about due to the development of greater intelligence and culture in our species, as when old people can contribute positively to the survival of their descendants there is a selection pressure that leads to a growing number of old people - a lengthening of life spans.

The satellite cells that support muscle tissue are one of the most studied stem cell populations. Certainly it is there that most of the really interesting discoveries have been made in recent years. For example that stem cell populations are not greatly diminishing in size, though there is some debate over this point in various different types of stem cell, and that the cells themselves are not becoming incapable of action. Rather the stem cell niche, the supporting tissue environment that houses these cells, changes over time and the stem cells become increasingly quiescent in response to altered levels of circulating proteins. We can speculate as to how these and other changes in the tissue environment are linked to the cellular and molecular damage that accumulates as a side-effect of the normal operation of metabolism. Figuring that out is very much a work in progress. Researchers have identified some of the specific protein signals involved in recent years, and have demonstrated that altering these signal levels can restore aged stem cells to a more youthful level of activity. You might look back in the Fight Aging! archives at work on GDF-11 and muscle stem cell rejuvenation, for example.

Obviously this is of great interest, as putting old stem cells back to work could ameliorate a range of age-related conditions. Just look at the benefits produced today via first generation stem cell therapies used to treated the old and the damaged. As is usually the case, we should expect there to be multiple mechanisms at work and multiple ways to influence any one underlying process in cell biology, however. Nothing is simple in metabolism, and all processes are networks of linked feedback loops and mechanisms. So here researchers report another method of restoring activity in aged muscle stem cells:

Why age reduces our stem cells' ability to repair muscle

[Researchers] 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 [the] 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. 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.

Researchers discover a key to making new muscles

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. 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."

Inhibition of JAK-STAT signaling stimulates adult satellite cell function

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 3-week-old relative to 18-month-old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases.

One concern in this approach of putting old stem cells back to work is the very same that has existed for all stem cell treatments, which is the risk of cancer. If stem cells decline in their activity because it reduces cancer risk, then overriding that behavior in an old body that still has a high level of cellular damage will probably raise the risk of cancer. This is an issue that has been successfully addressed in stem cell treatments to date, and I imagine it will be successfully addressed in future treatments based on making older stem cells act as though they are in young tissue. It is a concern and an additional cost of development, not a roadblock.

Indeed, with reference to this recent work on stem cell rejuvenation you don't have to look far to see that STAT3 levels are associated with cancer stem cells in a variety of cancers, though not in any straightforward fashion. Biology is always far more complicated than we would like it to be for the purposes of medicine.