P311 promotes type II transforming growth factor-beta receptor mediated fibroblast activation and granulation tissue formation in wound healing

Background: P311, a highly conserved 8 kDa intracellular protein, has recently been reported to play an important role in aggravating hypertrophic scaring by promoting the differentiation and secretion of fibroblasts. Nevertheless, how P311 regulates the differentiation and function of fibroblasts to affect granulation tissue formation remains unclear. In this work, we studied the underlying mechanisms via which P311 affects fibroblasts and promotes acute skin wound repair. Methods: To explore the role of P311, both in vitro and in vivo wound-healing models were used. Full-thickness skin excisional wounds were made in wild-type and P311(-/-) C57 adult mice. Wound healing rate, re-epithelialization, granulation tissue formation and collagen deposition were measured at days 3, 6 and 9 after skin injury. The biological phenotypes of fibroblasts, the expression of target proteins and relevant signaling pathways were examined both in vitro and in vivo. Results: P311 could promote the proliferation and differentiation of fibroblasts, enhance the ability of myofibroblasts to secrete extracellular matrix and promote cell contraction, and then facilitate the formation of granulation tissue and eventually accelerate skin wound closure. Importantly, we discovered that P311 acts via up-regulating the expression of type II transforming growth factor-beta receptor (TGF-beta RII) in fibroblasts and promoting the activation of the TGF-beta RII-Smad signaling pathway. Mechanistically, the mammalian target of rapamycin signaling pathway is closely implicated in the regulation of the TGF-beta RII-Smad pathway in fibroblasts mediated by P311. Conclusions: P311 plays a critical role in activation of the TGF-beta RII-Smad pathway to promote fibroblast proliferation and differentiation as well as granulation tissue formation in the process of skin wound repair. (C) Crown copyright 2022.