Muscling up on stem cells

LA JOLLA, Calif.—A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) describes the biology behind why muscle stem cells respond differently to aging or injury. The Jan. 4, article, entitled “Muscle Stem Cells Exhibit Distinct Clonal Dynamics in Response to Tissue Repair and Homeostatic Aging,” can be found in Cell Stem Cell. The research may have implications for therapeutic strategies to regenerate skeletal muscle in response to the normal wear and tear of aging, or in cases of injury or muscle diseases such as muscular dystrophy.

“Our study is one of the first to look at muscle stem cells in their native tissue with resolution at the level of a single clone,” Dr. Alessandra Sacco, professor at SBP, tells DDNews. “This allowed us to probe the dynamic heterogeneity of the cells, a measure of their flexibility to respond to exercise, injury and the normal wear and tear that occurs with aging. Using this approach, we found surprising differences in the degree to which stem cells can maintain this heterogeneity, depending on what they are asked to do.

“Studying muscle stem cells in their native tissues in vivo provides fundamental information on how the cells behave in the intact animal, and allows us to correlate their behavior with their anatomical location, i.e. proximity with other cell types. While strategies to isolate muscle stem cells from the tissue and culture them in vitro have provided invaluable information regarding their molecular regulators, in this experimental context they are removed from their environment, thus losing the spatial 3D information as well as the signals they are exposed to,” notes Sacco.

Adult muscle stem cells are essential for repairing and regenerating muscle throughout life. These cells are located between muscle fibers and exist as a heterogeneous population that self-renew to maintain the stem cell population, as well as differentiate into myogenic cells that proliferate, differentiate and fuse to create new muscle fibers. Sacco and her colleagues focused on studying how the pool of muscle stem cells responds to age or after an injury to the muscle.

“Our goal is to understand how stem cells uniquely cope with or yield to these different pressures. Then, we can use this information to create new approaches designed to specifically prevent muscle stem cell loss and/or dysfunction linked to sarcopenia, or in association with muscle diseases that are characterized by chronic tissue damage, such as dystrophies,” she adds.

Sacco’s research team used a technology called in-vivo multicolor lineage tracing to follow the self-renewal capacity and range of progeny produced by individual stem cells. Repetitive injuries cause muscles to undergo multiple rounds of repair, and are used as a model for diseases characterized by progressive muscle degeneration and weakness, such as muscular dystrophies.

“Multicolor lineage tracing is a tool that allows us to randomly label cells with different colors in a tissue. It has been invaluable for studying several stem cell compartments. In our study, we utilized it to specifically label muscle stem cells,” continues Sacco. “As the labeling is heritable, all the progeny of a given cell will have the same color. This allows us to follow how the progeny of individual cells contribute to the tissue and what is the extent of each clone’s contribution.”

“The results were quite different from what we expected—aged muscle stem cells maintained a diverse assortment of cells in the overall pool, despite being less able to proliferate and multiply sufficiently. The outcome was flipped when we caused an injury and watched how the pool responded to tissue damage,” explained Dr. Matthew Tierney, a former graduate student of Sacco, now a postdoctoral researcher at The Rockefeller University.

“In the case of injury, the stem cell pool becomes less diverse, but maintains its proliferative capacity. Our findings lead to several interesting questions about the potential causes of these observed differences—muscle stem cells are asked to function in a very different local environment with age or during regeneration due to injury, and we suspect this may contribute to some of the distinct behaviors we observed,” added Tierney.

Sacco notes that in part because of environmental factors, there probably isn’t a one-size-fits-all approach to prevent the decline of muscle stem cells. Therapeutic strategies to maintain muscle mass and strength in seniors will most likely need to differ from those for patients with degenerative diseases.

“This study is just a first step to start exploring muscle stem cell clonal composition. Future work will integrate these studies on muscle stem cell heterogeneity in order to develop novel approaches to enhance muscle stem cell function while maintaining their clonal composition, and potentially ameliorate muscle-wasting diseases,” Sacco concludes.