Study suggests healing skin without scarring may be possible

Good news!

"... The new study published March 20 in Cell reveals a way to fully regenerate skin by unblocking an embryonic healing mechanism that shuts off after birth. Demonstrated on mice, the strategy may help guide the development of similar therapies for human patients. ...

In mice wounded three days before birth, the skin regenerated diverse cell types and closely resembled unwounded skin.

But when wounded at five days after birth, the site was covered by epithelial cells and became packed with collagen scar tissue and abnormally dense nerve fibers and immune cells. Many other skin cell types failed to regrow. ...

They found that postnatal wound sites became densely packed with nerves. This “hyperinnervation” occurs because fibroblasts in postnatal wounds upregulate the gene Cxcl12, which recruits excessive nerves to the area and impairs the regrowth of other skin-cell types.

When researchers depleted Cxcl12 in wounds in postnatal mice, “hyperinnervation” was curtailed, and the skin regrew diverse cell types. Blocking local nerve signaling with botulinum toxin A (Botox) produced similar effects. ..."

From the highlights and abstract:

"Highlights

• Embryonic skin regenerates diverse cell types after injury, whereas postnatal skin does not

• Postnatal wounds have wound-specific fibroblasts that drive hyperinnervation via CXCL12

• Excessive innervation at the wound site blocks multilineage regeneration

• Reducing hyperinnervation restores multilineage regeneration after postnatal injury

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 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.

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Study suggests healing skin without scarring may be possible — Harvard Gazette "Researchers unblock embryonic regrowth mechanism that shuts down after birth in mice"

Hyperinnervation inhibits organ-level regeneration in mammalian skin (open access)

Graphical abstract

Figure 1 Multilineage regeneration differs between embryonic and postnatal wounding