Head muscle fibro-adipogenic progenitors account for the tilted regeneration towards fibrosis

Abstract

Branchiomeric head muscle is ontogenetically and phylogenetically distinct from somitic limb muscle, and they exhibit different regenerative capacity. Unique satellite cell property of head muscle could explain the impaired myofiber formation, but the underlying mechanism for fibrosis is still elusive. In this work, we first established a freezing-induced skeletal muscle regeneration model and made comparisons between the regeneration characteristics in tibialis anterior (TA) muscle and masseter (MAS) muscle. The process of myogenesis and fibrogenesis were investigated by histological, immunohistochemical and cellular analysis, to characterize the role of muscle satellite cell (MuSCs) and fibro-adipogenic progenitors (FAPs) in TA and MAS muscle regeneration. Our results revealed that FAPs infiltrated the fibrotic area during MAS muscle regeneration. In contrast to the rapid rise and fall of FAPs number at the early regeneration stages in TA muscle, the number of MAS FAPs increased to a plateau without descending till 14 days after injury. It is the first time that the pivotal role of FAPs in head muscle regeneration was characterized. The persistence of FAPs without timely clearance in the first two weeks of regeneration could be accountable for the head muscle fibrosis.