Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing

TY - JOUR

T1 - Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing

AU - Rognoni, Emanuel

AU - Gomez, Celine

AU - Pisco, Angela Oliveira

AU - Rawlins, Emma L

AU - Simons, Ben D

AU - Watt, Fiona M

AU - Driskell, Ryan R

PY - 2016/7/15

Y1 - 2016/7/15

N2 - New hair follicles (HF) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we made small (2mm diameter) circular wounds and monitored HF formation at the wound site. At P2 new follicles formed in back skin, but follicle formation was markedly decreased by P21. Neonatal tail also formed wound-associated follicles, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50 fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared to P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds while β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.

AB - New hair follicles (HF) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we made small (2mm diameter) circular wounds and monitored HF formation at the wound site. At P2 new follicles formed in back skin, but follicle formation was markedly decreased by P21. Neonatal tail also formed wound-associated follicles, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50 fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared to P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds while β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.

KW - Fibroblast lineages

KW - Wounding

KW - β-catenin

UR - http://www.scopus.com/inward/record.url?scp=84978701088&partnerID=8YFLogxK

U2 - 10.1242/dev.131797

DO - 10.1242/dev.131797

M3 - Article

C2 - 27287810

SN - 0950-1991

VL - 143

SP - 2522

EP - 2535

JO - Development (Cambridge): for advances in developmental biology and stem cells

JF - Development (Cambridge): for advances in developmental biology and stem cells

IS - 14

ER -