Wn1-Lineage Fap Regulates Orofacial Muscle Regeneration By Outcompeting ASC

Orofacial muscle is prone to fibrosis, but the underlying mechanism is elusive. Fibro-adipogenic progenitor (FAP) and subcutaneous adipose stromal cell (ASC) [1], mesenchymal stem cells in skeletal muscle regeneration with contrary effects, could interact with each other based on the elite clone competition theory to determine the outcome of orofacial muscle regeneration. [1] Quentin Sastourné-Arrey, Maxime Mathieu, Xavier Contreras, et al. Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury. Nat Commun. 2023;14(1):80. Subcutaneous adipose tissue from Prrx1-GFP reporter mice was grafted to Wnt1-YFP reporter mice, followed by freezing-induced orofacial muscle injury. Spatial transcriptomics, combined with in vitro and in vivo validation experiments were conducted to investigate the regulatory role of Myc in defining FAP-ASC interaction and the outcome of orofacial muscle regeneration. Histological analysis and transcriptomics revealed that Wnt1-lineage FAP outcompeted ASC in orofacial muscle regeneration. Myc determines the super-competitor role of FAP and Myc-wnt signaling pathway in FAP led to orofacial muscle fibrosis. Myc could serve as a potential intervention target to reverse the competitive disadvantage of ASC to counteract muscle fibrosis. The study elaborates the complete molecular mechanism of Wnt1-lineage FAP in regulating orofacial muscle fibrosis, thus opening up new perspectives and treatment paradigms for promoting effective regeneration of orofacial muscles, which could ultimately contribute to the improvement even revolution in plastic and reconstructive surgeries in the orofacial region.