Hedgehog Signaling in Papillary Fibroblasts Is Essential for Hair Follicle Regeneration during Wound Healing

Sophie Frech,Agnes Forsthuber,Ana Korosec,Katharina Lipp,Viktor Kozumov,Beate M Lichtenberger

doi:10.1016/j.jid.2021.11.026

Sophie Frech, Agnes Forsthuber + Show 4 more

Open Access

https://doi.org/10.1016/j.jid.2021.11.026

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Abstract

Patients suffering from large scars such as burn victims not only encounter aesthetic challenges but also ongoing itching or pain that substantially deteriorates their quality of life. Skin appendages such as hair follicles rarely regenerate within the healing wound. Because they are crucial for skin homeostasis and the lack thereof constitutes one of the main limitations to scarless wound healing, their regeneration represents a major objective for regenerative medicine. Fibroblasts, the main resident cell type of the skin dermis, mediate embryonic hair follicle morphogenesis and are particularly involved in wound healing because they orchestrate extracellular matrix remodeling and collagen deposition in the wound bed. Importantly, dermal fibroblasts originate from two distinct developmental lineages with unique functions that differently mediate the response to epidermal signals such as Hedgehog signaling. In this study, we show that Hedgehog signaling in the reticular fibroblast lineage promotes the initial phase of wound repair, possibly by modulating angiogenesis and fibroblast proliferation, whereas Hedgehog signaling in papillary fibroblasts is essential to induce de novo hair follicle formation within the healing wound.

Highlights

Embryonic and early fetal skin heal by regeneration, while postnatal wounds typically form a scar lacking skin appendages such as hair follicles (HFs) (Bullard et al 2003; Leavitt et al 2016)
By genetically deleting or activating Smoothened (Smo), one of the main activating protagonists of the Hh-pathway, either in all dermal fibroblasts or exclusively in Fpap, we demonstrate that Hh-signalling in fibroblasts of the reticular lineage (Fret) promotes wound closure
In this study, we demonstrate that modulation of Hh-signalling in distinct dermal fibroblast lineages differently affects wound healing and WIHN

Summary

Introduction

Embryonic and early fetal skin heal by regeneration, while postnatal wounds typically form a scar lacking skin appendages such as hair follicles (HFs) (Bullard et al 2003; Leavitt et al 2016). De novo HFs form only under particular circumstances such as in large wounds (wounding-induced hair follicle neogenesis, WIHN) (Ito et al 2007; Lim et al 2018; Phan et al 2020; Rognoni et al 2016) or upon modulation of embryonic signalling pathways including epidermal Wnt/ -catenin activation Concomitant Hh-pathway activation in adjacent epithelial and stromal cells is sufficient to induce new HFs in intact hairless skin (Sun et al 2020). Embryonic HF development is initiated by self-organizing dermal cells of the papillary fibroblast lineage (Fpap) that form the dermal condensate (DC). Fibroblasts of the reticular lineage (Fret) but not Fpap are capable of differentiating into adipocytes (Driskell et al 2013; Festa et al 2011; Korosec et al 2018; Mastrogiannaki et al 2016). Fret mediate the initial phase of wound healing by depositing and reorganizing collagens and other extracellular matrix (ECM) molecules, while Fpap populate the wound only after reepithelialization has occurred (Driskell et al 2013), which is likely why healed wounds lack

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