During tissue repair, myofibroblasts produce extracellular matrix (ECM) molecules for tissue resilience and strength. Altered ECM deposition can lead to tissue dysfunction and disease. Identification of distinct myofibroblast subsets is necessary to develop treatments for these disorders. Here, using extensive analysis of pro-fibrotic cells during mouse skin wound healing, fibrosis and aging; we identify distinct subpopulations of myofibroblasts, including cells identified as adipocyte precursors (APs). Multiple mouse models and transplantation assays demonstrate that AP proliferation, and not other myofibroblasts, is activated by CD301b-expressing macrophages through IGF1 and PDGFC. With age, wound bed APs and differential gene expression between myofibroblast subsets are reduced. Our findings identify multiple fibrotic cell populations and suggest the environment dictates functional myofibroblast heterogeneity, which is driven by fibroblast-immune interactions after wounding.

Highlights d Inhibiting dermal adipocyte lipolysis reduces inflammatory wound bed macrophages d Wound edge adipocytes dedifferentiate within hours after injury d Adipocyte lipolysis is needed for dedifferentiated adipocytes to populate wound beds d Dedifferentiated adipocytes generate wound bed myofibroblasts after injury

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