Postnatal Pax7-expressing limb cells are multipotent and generate non-myogenic lineages that persist into adulthood

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 Pax7 ^FAPs 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 Pax7 ^FAPs persist into adulthood. In addition, injury in adult muscle triggered de novo generation of Pax7 ^FAPs , 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.