The molecular regulation of muscle stem cell function

Abstract

Muscle satellite cells are responsible for the postnatal growth and robust regeneration capacity of adult skeletal muscle. A subset of satellite cells purified from adult skeletal muscle is capable of repopulating the satellite cell pool, suggesting that it has direct therapeutic potential for treating degenerative muscle disease. Satellite cells uniformly express the transcription factor Pax7, and Pax7 is required for satellite cell viability and to give rise to myogenic precursors that express the basic helix-loop-helic (bHLH) transcription factors Myf5 and MyoD. Pax7 activates expression of target genes such as Myf5 and MyoD through recruitment of the Wdr5/Ash2L/MLL2 histone methyltransferase complex. Extensive genetic analysis has revealed that Myf5 and MyoD are required for myogenic determination, whereas myogenin and MRF4 have roles in terminal differentiation. Using a Myf5-Cre knockin allele and an R26R-YFP Cre reporter, we observed that in vivo about 10% of satellite cells only express Pax7 and have never expressed Myf5. Moreover, we found that Pax7(+)/Myf5(-) satellite cells give rise to Pax7(+)/Myf5(+) satellite cells through basal-apical asymmetric cell divisions. Therefore, satellite cells in skeletal muscle are a heterogeneous population composed of satellite stem cells (Pax7(+)/Myf5(-)) and satellite myogenic cells (Pax7(+)/Myf5(+)). Evidence is accumulating that indicates that satellite stem cells represent a true stem cell reservoir, and targeting mechanisms that regulate their function represents an important therapeutic strategy for the treatment of neuromuscular disease.