Yi, C.; Liu, X.; Wang, L.; Song, L.; Fei, J.-F.

The precise regulation of muscle stem cell (MuSC) plasticity remains poorly understood. While studies have suggested that Pax7+ MuSCs in vertebrate limbs are committed solely to myogenic lineages during regeneration, we previously observed during axolotl tail regeneration, Pax7+ MuSCs contribute to the fibroblast and chondrocyte mesodermal lineages. However, the underlying mechanism is unclear. Here, we show that the duration of ERK signaling plays an important role in MuSCs cell fate. We observed that ERK exhibits sustained activation after tail amputation that is followed by subsequent inhibition. We found that ERK activation initiates MuSCs plasticity switch toward a trunk fibroblast fate by repressing PAX7 expression. However, subsequent inhibition of ERK activity is essential for the transition of trunk fibroblast to fin fibroblast targeting PRRX1. In addition, we found that the TGF-{beta}/SMAD2 cascade as a downstream mediator of ERK-driven regulation of MuSC plasticity towards fibroblast and chondrocyte during tail regeneration. Together, we uncovered a new phased stem cell regulatory mechanism linking injury-induced ERK signaling to stem cell plasticity regulation, offering new insights with potential implications for regenerative medicine.