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

Abstract

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.

Fibroblast heterogeneity: implications for human disease

“…Changes are also prominent in other components of connective tissue such as the large blood vessels. In the skin, proliferation of fibroblasts occurs during mouse embryonic development; however, subsequent growth of the animal is not associated with further fibroblast proliferation and is instead achieved simply by an increase in the ECM volume between adjacent fibroblasts (109). This is consistent with the observation that the rate of fibroblast division in the adult dermis is very low in the steady state (137).…”

“…β-Catenin stabilization in dermal fibroblasts during development leads to fibrosis and impairs adipogenesis (108). Wnt/β-catenin expression in the adult dermis inhibits de novo hair follicle formation in healing wounds, and postnatal ablation of β-catenin in dermal fibroblasts enhances new hair formation (109). Additional signaling pathways that have been implicated in the regulation of dermal fibroblasts include the Notch pathway, which has a role in the regulation of inflammation and hair follicle morphogenesis (110,111).…”

Inhibition of β-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C-82

“…In contrast to studies with mice, where β-catenin signaling in the skin was blocked, in the present study we did not see an effect of β-catenin inhibition on hair follicle formation (Rognoni et al, 2016). Wnt/β-catenin signaling plays key roles in hair follicle development and maturation (Hsu et al, 2014).…”

Concise Review: Translating Regenerative Biology into Clinically Relevant Therapies: Are We on the Right Path?

“…These findings support fibroblast identity as a key component of regeneration, similar to how fibroblasts from different dermal layers or anatomical regions differentially contribute to wound healing [66,76]. Similarly, in most mammals the ability to regenerate hair follicles in full-thickness skin wounds is lost during ontogeny and can be traced to changes in fibroblast signaling patterns, specifically a downregulation of Wnt signals and an upregulation of inflammatory cytokines in mature fibroblast populations [94]. However, studies using the Mus digit tip model suggest that fibroblasts from normally nonregenerative amputation levels maintain the ability to respond to appropriate patterning signals as both P2 and P3 digit cells show similar expression of BMP receptors and SMAD activation [95], and addition of exogenous BMP2 and BMP7 in vivo is able to induce skeletal patterning in nonregenerative amputations of neonatal and adult mice [40,[96][97][98].…”