Fibroadipogenic Progenitor–Secreted Prostaglandin E2 Coordinates Stem Cell Fate via Autocrine and Paracrine Crosstalk in Healthy and Dystrophic Muscle.

FAP-secreted PGE2 exerts paracrine effects that maintain the muscle stem cell pool at steady state and stimulate their proliferation post-injury. Moreover, it has autocrine effects that influence FAP fate decisions and promote their apoptosis. Administration of non-steroidal anti-inflammatory drugs that inhibit the prostaglandin-synthesizing enzyme COX2 increases FAPs content post-injury.

Using Pdgfrα-CreERT2_Cox2flox mice, we showed that conditional ablation of COX2 specifically in FAPs increases FAPs content, fibrosis, and impairs muscle regeneration, which can be rescued by PGE2 administration. Furthermore, we show that PGE2 production in FAPs is impaired in mouse models of Duchenne muscular dystrophy, and we provide a proof-of-concept that PGE2 administration can reduce FAPs numbers, fibrosis accumulation, and increase muscle strength.

Overall, we uncover a novel role for PGE2 beyond its function in inflammation and identify a mechanism by which FAPs intrinsically regulate their own cell fate, revealing therapeutic potential for muscle injury and dystrophic conditions.