BMP2-induced Adam12 ⁺ Fibroblasts Dictate Wound-associated Skin Scarring and Fibrosis

Skin wounds typically undergo healing through scar formation, a fibrotic process mainly mediated by fibroblasts. Cumulative evidence from our group and others has established that Adam12⁺ fibroblasts were upregulated following skin injury and played a crucial role in scar formation. However, the molecular mechanisms governing the origin and pathogenesis of Adam12⁺ fibroblasts during skin scarring remain elusive. Here, we demonstrated that Adam12⁺ fibroblasts were necessary for wound-associated skin scarring and fibrosis. We identified BMP2 as the essential upstream signal for the generation of Adam12⁺ fibroblasts from resident fibroblasts and periostin as the key downstream effectors. Fibroblast-specific conditional knockout of BMP2 receptor significantly reduced Adam12⁺ fibroblast population, periostin expression, and ultimately skin scarring and fibrosis post-injury. BMP2, periostin and Adam12⁺ fibroblasts were found to be increased significantly in pathological scars compared with normal scars, and augmentation of BMP2 signaling expanded Adam12⁺ fibroblast population and exacerbated skin scarring and fibrosis, suggesting that BMP2 overexpression may contribute to pathological scarring. Pharmacological inhibition of BMP2 signaling markedly attenuated pathological scars. Taken together, our findings will help to understand skin fibrosis pathogenesis and provide potential targets for the therapy of pathological scars.