Hyperinnervation inhibits organ-level regeneration in mammalian skin
Summary
Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration-restoring diverse cell types across lineages-remains rare. Here, we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper connectivity. However, this ability is lost soon after birth, resulting in failure to restore most cell types and hyperinnervation within the wound bed. Single-cell sequencing identified a
Content
# Hyperinnervation inhibits organ-level regeneration in mammalian skin
*Published: 2026 Mar 20*
Some mammalian tissues can replace lost cells within one lineage, but
organ-level regeneration-restoring diverse cell types across lineages-remains
rare. Here, we show that late embryonic full-thickness skin injuries heal by
regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper
connectivity. However, this ability is lost soon after birth, resulting in
failure to restore most cell types and hyperinnervation within 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 that three PWF-enriched genes-Timp1, Cxcl12, and Ccl7-inhibit
organ-level regeneration and cause hyperinnervation when overexpressed in
embryonic wounds. Reducing hyperinnervation in postnatal wounds through the
depletion of Cxcl12 in fibroblasts or nerve ablation enables regeneration of
diverse lineages after injury. Our study identifies mechanisms that transition
an organ from regenerative to non-regenerative, discovers fibroblast-driven
hyperinnervation as a key barrier, and demonstrates that removing this barrier
unlocks organ-level regeneration.
DOI: 10.1016/j.cell.2026.02.027