Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing

Chae Ho Lim,David H Wang,Wendy Lee,M Mark Taketo,Jason E Cain,Soung-Hoon Lee,Piul Rabbani,Sarah Millar,D Neil Watkins,Qi Sun,Karan Ratti,Makoto Takeo,Mayumi Ito,George Cotsarelis,Maksim V Plikus,Peggy Myung,Ying Zheng

doi:10.1038/s41467-018-07142-9

Abstract

Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal.

Highlights

Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration
Sonic hedgehog (Shh) signaling is essential for wound-induced HF neogenesis
Shh expression during hair follicle morphogenesis is conserved between mice and humans[15] and vital for hair follicle development and hair cycle[14,16,17,18,19,20,21,22]

Summary

Introduction

Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. Small skin excisions in mice result in the formation of scar tissue, or fibrosis, which is composed largely of extracellular matrix components like collagens and fibronectin and devoid of new accessory structures like HFs11 (Supplementary Fig. 1a–g). Both large and small human skin wounds incurred by trauma or dystrophy almost always undergo fibrotic scarring. Our study suggests that the absence of regenerative cues impacts the inability of hair follicle morphogenesis after injuring the skin

Methods

Results

Conclusion