LYin H, Price F, Rudnicki MA. Satellite Cells and the Muscle Stem Cell Niche. Physiol Rev 93: 23-67, 2013; doi:10.1152/physrev.00043.2011.-Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process involving the activation of various cellular and molecular responses. As skeletal muscle stem cells, satellite cells play an indispensible role in this process. The self-renewing proliferation of satellite cells not only maintains the stem cell population but also provides numerous myogenic cells, which proliferate, differentiate, fuse, and lead to new myofiber formation and reconstitution of a functional contractile apparatus. The complex behavior of satellite cells during skeletal muscle regeneration is tightly regulated through the dynamic interplay between intrinsic factors within satellite cells and extrinsic factors constituting the muscle stem cell niche/microenvironment. For the last half century, the advance of molecular biology, cell biology, and genetics has greatly improved our understanding of skeletal muscle biology. Here, we review some recent advances, with focuses on functions of satellite cells and their niche during the process of skeletal muscle regeneration.

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of murine adult satellite cells to contribute to regeneration and repopulate the niche. Gene expression analysis identified an increase in expression of JAK/STAT signaling targets between 3 week old and 18 month old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Knockdown of Jak2 or Stat3 in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche. Pharmacological inhibition of Jak2 and Stat3 similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a dramatic enhancement of muscle repair and force generation. Together these results reveal intrinsic properties that functionally distinguish adult satellite cells and suggest a promising therapeutic avenue for the treatment of muscle wasting diseases.

SUMMARY Spinal Muscular Atrophy (SMA) is caused by mutations in the SMN1 gene. Because this gene is ubiquitously expressed, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To address this question, we carried out RNA-sequencing studies using fixed, antibody-labeled and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the endoplasmic reticulum (ER) stress pathway. Functional studies demonstrated that inhibition of ER stress improves MN survival in vitro even in MNs expressing low SMN. In SMA mice, systemic delivery of an ER stress inhibitor that crosses the blood-brain-barrier led to preservation of spinal cord MNs. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable for studying disease-prone human cells in heterogeneous cultures.