An ERK-dependent molecular switch antagonizes fibrosis and promotes regeneration in spiny mice ( Acomys )

Abstract Although most mammals heal wounds with scar tissue, spiny mice ( Acomys cahirinus ) naturally regenerate skin and complex musculoskeletal tissues. The core signaling pathways driving mammalian tissue regeneration are poorly characterized. Here, we show that MAPK/ERK signaling acts as a major hub directing cellular injury responses towards regeneration. While immediate ERK activation was a shared feature of scarring ( Mus musculus ) and regenerating ( Acomys ) wounds, ERK activity was only sustained during regeneration. Upon ERK inhibition, the Acomys wound microenvironment exhibited key hallmarks of fibrosis, including a pro-scarring matrisome, epidermal differentiation and reduced proliferation. These findings indicate that ERK inhibition shifts tissue regeneration towards fibrosis. Conversely, the ectopic release of ERK activators (FGF/Neuregulin) in fibrotic scars, stimulated a pro-regenerative matrisome, cell proliferation and hair follicle neogenesis, thus promoting skin regeneration. Our data provide new insights into why some mammals regenerate better than others and open avenues to reverse fibrosis in favor of regeneration. Teaser FGF2 and NRG1 stimulate skin and hair follicle regeneration through ERK-mediated control of cell behavior in adult mammals.