Abstract
Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.
Highlights
Skeletal muscles are essential for physiological functions such as locomotion, breathing, and metabolism, and they represent up to 40% of the human body mass
Adult skeletal muscles are regenerated upon injury by muscle stem cells (MuSCs)
MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined
Summary
Skeletal muscles are essential for physiological functions such as locomotion, breathing, and metabolism, and they represent up to 40% of the human body mass. They are activated upon muscle injury, proliferate and differentiate to contribute to new muscle fibers, or self-renew to reconstitute the stem cell pool [31,32,33,34]. This process is accompanied by a temporal expression of cell fate markers, such as the transcription factors Pax (stem), Myod (commitment) and Myogenin (differentiation). Adult EOM-derived MuSCs cells have superior in vitro proliferation, self-renewal and differentiation capacities, as well as a superior in vivo engraftment potential, compared to limb-derived MuSCs [39]. The unique functional properties of adult EOM MuSCs remain undefined at the molecular level, and it is unclear if their specificity is instructed by cell-intrinsic factors or through interactions with their microenvironment (niche)
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