Gioftsidi, S.; Hayashi, T.; Fall, S.; Jagot, S.; Dos Santos, M.; Le Grand, F.; Relaix, F.; Mourikis, P.

Organs are composed of a complex arrangement of diverse cell types that can originate from independent cell lineages or shared progenitors. Skeletal muscle is derived from mesodermal Pax7+ stem/progenitor cells that can differentiate into myoblasts to form muscle fibers. During embryogenesis, however, somitic Pax7+ cells can also give rise to non-muscle cell types, including dermis and adipocytes. Here, we asked whether Pax7+ cells retain such multipotency during early postnatal growth of limb muscles. Using lineage tracing, we uncovered unexpected plasticity at early postnatal days, leading to the generation of multiple non-myogenic lineages, including a previously unrecognized Pax7-derived subpopulation of fibro-adipogenic progenitors that we termed Pax7FAPs and further investigated. Using mouse models, we further show that Notch signaling primes neonatal Pax7 cells toward a fibrogenic molecular identity at the expense of myogenic differentiation, thereby biasing their trajectory toward a fibrogenic fate. In the adult muscle, long-term tracing revealed that neonatally produced Pax7FAPs persist into adulthood. In addition, injury in adult muscle triggered de novo generation of Pax7FAPs, which displayed higher proliferative capacity than resident stromal cells. This newfound multipotency of postnatal Pax7+ cells adds a new dimension to our understanding of cellular contributions during postnatal muscle development and regeneration.