Hyperinnervation inhibits organ-level regeneration in mammalian skin

Here we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular lineages with proper connectivity. However, this ability is lost soon after birth, leading to a failure to restore most cell types and hyperinnervation of the wound bed.

Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered three PWF-enriched genes—Timp1, Cxcl12, and Ccl7—that inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation by depleting Cxcl12 in fibroblasts or inhibiting synaptic release enables postnatal skin to regenerate diverse lineages after injury.