Mechanisms Regulating Muscle Stem Cell Homeostasis

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Skeletal muscle tissue is repaired and maintained for the lifetime of mammalian organisms but can be compromised by diseases and in aged individuals. The adult stem cell responsible for regenerating and main- taining skeletal muscle tissue is the rare satellite cell, comprising 2-4% of the total muscle nuclei. The satellite cell is named for its anatomical localization in skeletal muscle tissue, where these cells are typically quiescent and lie sandwiched between the plasma membrane of the myofiber and the basement membrane. When in- jured, the quiescent satellite cell responds by sequentially “activating,” entering the cell cycle, proliferating as progenitors and then undergoing terminal differentiation and fusion to repair damaged myofibers or fusion with each other to form new myofibers. A small number of satellite cells self-renew, re-acquiring a quiescent state and re-occupying the satellite cell niche to provide continuous maintenance and repair. The severity of a muscle injury recruits satellite cells, which expand to repair the damage and then, return to pre-injury numbers once regeneration is completed. What signals are responsible for terminating satellite cell expansion during regeneration? When do satellite cells self-renew in vivo? How does the “severity” of a muscle injury recruit sat- ellite cells? What mechanisms ensure that satellite cells are re-established at pre-injury numbers once regener- ation is complete? We have identified a cell-cell interaction between satellite cells and invading cells appearing between 4 days and 7 days following a muscle injury that appears to regulate satellite cell numbers. The num- bers of invading cells directly correlate with the severity of a muscle injury and thus, may regulate satellite cell numbers commensurate with injury severity. We posit that a cell non-autonomous response to a muscle injury conveys the extent of muscle damage directly to the expanding satellite cells, enabling the stem cells to appro- priately respond and ensuring the appropriate numbers of progenitors are available for repair and for self-re- newal to repopulate the stem cell pool. If confirmed, the cell non-autonomous regulation of the skeletal muscle stem cell pool represents a new paradigm for conveying the extent of tissue damage to a resident stem cell and will identify new therapeutic targets to manipulate satellite cell number and potentially improve cell transplan- tation as well as muscle regeneration.