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Some mammalian tissues can replace lost cells within a lineage, but organ-level regeneration - that is, the restoration of diverse cell types across lineages - remains rare. This study shows that full-thickness skin damage in late embryos heals through normal connections of epithelial, mesenchymal, neuronal and vascular tissues. However, this ability is lost shortly after birth, resulting in the inability to restore most cell types and the presence of excessive neural innervation in the wound bed. Single-cell sequencing revealed the postnatal wound-specific fibroblast (PWF) population that was missing after embryonic injury. Through in vivo screening, we found that the three genes enriched in PWF - Timp1, Cxcl12 and Ccl7 - were overexpressed in embryonic wounds and inhibited organ-level regeneration and caused excessive neural innervation. By depleting Cxcl12 in fibroblasts or neuro-ablation, we reduced excessive neural innervation in postnatal trauma, allowing for the regeneration of diverse lineages after injury. Our study identified the mechanism by which organs transition from regenerative to non-regenerative, discovered that high neural innervation driven by fibroblasts is a key obstacle, and proved that eliminating this barrier can unlock organ-level regeneration. This study was published in Cell under the title "Hyperinnervation inhibits organ-level regeneration in mammalian skin".
References:
DOI: 10.1016/j.cell.2026.02.027
