The population of stem cells that supports muscle tissue is one of the better studied classes of such cell. Stem cells enable tissue maintenance and regeneration by delivering a supply of new daughter somatic cells that can multiple to make up losses, and through signaling that alters cell behavior. This activity declines with advancing age, however, with stem cells spending ever more of their time in a quiescent state. This is thought to be a response to rising levels of cell damage and tissue dysfunction, behavior that evolved because it serves to reduce the risk of cancer over a period in which our ancestors were under selection pressure for greater longevity. Cancer is a numbers game: more damage, more cell replication, and more cells all raise the odds of a cancerous mutation taking place.
Up close, the dynamics of stem cell behavior within the trend of age-related decline are anything but simple and uniform. The more data that researchers obtain, the more complexity they uncover. Biology is rarely as simple as the present understanding, and never as simple as would be convenient for the development of new therapies. Nonetheless, reliable manipulation of muscle stem cells is an important goal because it should enable some degree of reversal of age-related loss of muscle mass and strength, the condition known as sarcopenia.
There are many different layers of muscle biology at which benefits might be obtained. These range from the brute force approach of myostatin blockade, to put a thumb on the higher level controlling mechanisms that govern when muscle growth takes place at all, to adjusting the internal behavior of stem cells to make them more readily active, to repairing the underlying cell and tissue damage that causes stem cells to retreat from youthful levels of activity. Some of these methodologies are closer to realization than others; as a general rule, therapies that bypass the need for more detailed knowledge of these stem cell populations can make it to the clinic more rapidly.
"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. 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."
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 need to "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. "Here, we 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."
The research team followed the self-renewal capacity and range of progeny produced by individual stem cells. "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. 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."
Emerging evidence supports a significant functional heterogeneity in adult stem cell compartments. Single-cell studies in several tissues have revealed a range of behavioral capacities with regard to proliferation, self-renewal, and differentiation potential. This heterogeneity has been proposed as a beneficial feature of stem cells, which must rapidly adjust to the changing demands of their host tissue. By maintaining a spectrum of functional abilities, stem cells are better prepared to respond to various tissue repair scenarios while contributing to homeostatic turnover.
Single-cell lineage tracing offers a powerful means of studying functional heterogeneity in stem cells. Prior lineage tracing studies in vivo have demonstrated a broad array of clonal histories in different tissues. Modeling efforts leveraging these clonal datasets have begun to describe the dynamics of stem cell hierarchies. Intriguingly, several groups have described a loss of clonal complexity, or the diversity of stem cells in a pool or niche with distinct clonal origin, with accumulated stem cell activity. However, much of this work has taken place during youthful tissue homeostasis, and thus, little is known about how different environmental settings may alter the rate of this decline over time, including aging or wound healing. Moreover, the impact that reductions in clonal complexity may have on functional heterogeneity and stem cell behavior is still unclear.
To answer these questions, it is critical to study both aspects of individual stem cell behavior as part of the greater whole, particularly within a readily manipulated host tissue. To this end, skeletal muscle is well suited to examine changes in stem cell heterogeneity in response to disruptive or pathological settings. Skeletal muscle contains a bona fide stem cell population, termed muscle stem cells (MuSCs) or satellite cells, distributed throughout the tissue in their niche, where they remain poised to activate and contribute to cellular turnover.
To determine the impact of homeostatic aging and tissue repair on MuSC clonal complexity, we longitudinally assessed individual MuSC fate over time using in vivo multicolor lineage tracing. Surprisingly, we demonstrated that clonal complexity is largely preserved with homeostatic aging despite reductions in proliferative heterogeneity. Conversely, biostatistical modeling revealed that MuSCs undergo symmetric expansion and stochastic cell fate acquisition specifically during tissue repair, predicting neutral competition between clones resulting in clonal drift, or an increasingly small number of dominant clones. Accordingly, we observed that sustained regenerative pressure resulted in a progressive reduction in clonal complexity. Overall, this work establishes the importance of context in defining the principles underlying stem cell dynamics in skeletal muscle.