Director: Andrew Brack, PhD
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research Department of Orthopaedic Surgery
University of California, San Francisco
35 Medical Center Way
San Francisco, CA 94143
We focus on the molecular pathways that control cell fate decisions of the adult muscle stem cell (the satellite cell) to effectively regenerate adult skeletal muscle. In uninjured muscle, the rare satellite cells are in a functionally dormant, quiescent state. Upon an injury stimulus, these cells proliferate and their progeny will either differentiate to form new muscle fibers or undergo self renewal to replenish the stem cell pool. We believe that the temporally coordinated cell fate decisions of the stem cell and its progeny are reliant on the communication between the local environment (the muscle stem cell niche) and the stem cell itself. We are using cre/lox gene recombination and genetic knock in technology to deconstruct the communication between the niche and the muscle stem cell to investigate the cell fate decision making process during regeneration. In the future we hope this will lead to strategies that improve stem cell based therapies targeting aging and muscle disease.
Quiescence and self-renewal
Maintenance and reacquisition of quiescence are defining features of adult stem cells. We are studying the intrinsic and extrinsic factors that control quiescence and how they impinge on self-renewal and differentiation potential during muscle homeostasis, injury response and aging. Using a muscle stem cell specific mutant we demonstrated that Sprouty1 (Spry1), an RTK signaling inhibitor, is required for the reestablishment of quiescence in proliferating stem cells. We are presently identifying intrinsic and niche-derived signals that promote and retain stem cell potential.
Stem cell niche
The stem cell niche as originally conceptualized refers to the microenvironment that maintains ‘stemness’. The niche is a protector of stem cell number and function restraining proliferation and differentiation of stem cells and maintaining a quiescent phenotype. The satellite cell niche may be composed of different cell types. We are presently identifying the cell types and the essential signaling elements that compose the niche to retain stemness after injury and are deregulated during aging.
Satellite cell heterogeneity
It is apparent that adult stem cell populations are heterogeneous. Using a marker of proliferative history, based on retention of a fluorescent marker, we recently demonstrated that the adult satellite cell pool is composed of subsets of cells that are slowly dividing during ontogeny. Label retaining cells possess the properties of stem cells; in contrast, satellite cell subsets that diluted label functioned as progenitors. During aging a subset of functional label retaining cells are preserved. Current projects are deciphering whether heterogeneity is due to extrinsic influences, such as discrete niches, or cell intrinsic regulation, such as epigenetic and metabolic status.
Aging is associated with a progressive decline in many tissues throughout the body. Skeletal muscle is no exception. We are studying the mechanisms that lead to a loss of stem cell number and function during aging.
Human muscle stem cells and regeneration
Our understanding of muscle regeneration capacity and the regulation of stem and progenitor cells derive from largely from murine studies. We are beginning an expansive program to understand how human skeletal muscle homeostasis and repair are controlled at the cellular and molecular level.