Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing.
New hair follicles (HFs) 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 monitored HF formation at small circular (2 mm) wound sites. At P2, new HFs formed in back skin, but HF formation was markedly decreased by P21. Neonatal tail also formed wound-associated HFs, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with a 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 with P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds, whereas 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.
King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK.
Emanuel
0000-0001-6050-2860
E
Rognoni
King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK.
Celine
C
Gomez
King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK.
Angela Oliveira
AO
Pisco
Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Emma L
EL
Rawlins
Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Ben D
BD
Simons
King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK fiona.watt@kcl.ac.uk ryan.driskell@kcl.ac.uk.
Fiona M
0000-0001-9151-5154
FM
Watt
King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK fiona.watt@kcl.ac.uk ryan.driskell@kcl.ac.uk.
Ryan R
0000-0001-7673-2564
RR
Driskell
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002999:Clone Cells; D020405:Dermis / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018859:Hair Follicle / Q000502:physiology*; D006706:Homeostasis; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D038081:Organogenesis / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013623:Tail; D013997:Time Factors; D060449:Wnt Signaling Pathway; D014945:Wound Healing / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
D015415:Biomarkers; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; C045073:Cre recombinase; D019426:Integrases
Fibroblast lineages; Wounding; β-catenin