Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages.

Beate M Lichtenberger,Fiona M Watt,Maria Mastrogiannaki

doi:10.1038/ncomms10537

Abstract

Sustained epidermal Wnt/β-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs). This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. Here we show that epidermal Hedgehog (Hh) and Transforming growth factor-beta (TGF-β) signalling mediate the dermal changes. Pharmacological inhibition or genetic deletion of these pathways prevents β-catenin-induced dermal reprogramming and EF formation. Epidermal Shh stimulates proliferation of the papillary fibroblast lineage, whereas TGF-β2 controls proliferation, differentiation and ECM production by reticular fibroblasts. Hh inhibitors do not affect TGF-β target gene expression in reticular fibroblasts, and TGF-β inhibition does not prevent Hh target gene induction in papillary fibroblasts. However, when Hh signalling is inhibited the reticular dermis does not respond to epidermal β-catenin activation. We conclude that the dermal response to epidermal Wnt/β-catenin signalling depends on distinct fibroblast lineages responding to different paracrine signals.

Highlights

Sustained epidermal Wnt/b-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs)
By 2 weeks, the fibroblasts had colonized the full thickness of the dermis, as visualized by labelling for the pan-fibroblast marker, Platelet-derived growth factor receptor alpha (Pdgfra) (Fig. 1b,c)
Fibroblasts isolated from neonatal skin expanded more extensively in neonatal than adult telogen de-epidermized dermis (DED) at all three seeding densities and both time points tested (Fig. 1d), demonstrating that the dermal extracellular matrix (ECM) had an impact on fibroblast proliferation

Summary

Introduction

Sustained epidermal Wnt/b-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs) This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. We find that on Wnt/b-catenin activation, the epidermis expresses Sonic hedgehog (Shh), which stimulates proliferation and ECM remodelling by the papillary dermis, whereas the reticular dermis responds to epidermal Transforming growth factor (TGF)-b. These findings are of particular interest, given the many different epithelial tumours in which there is inappropriate activation of Wnt signalling accompanied by changes in the underlying connective tissue[8,9,10]

Methods

Results

Conclusion