GDNF promotes hair formation and cutaneous wound healing by targeting bulge stem cells

Sri Ramulu Pullagura,Robert E Braun,Manju Sharma,Thomas S Lisse,Neda Vishlaghi

doi:10.1038/s41536-020-0098-z

Abstract

Glial-cell-derived neurotrophic factor (GDNF) is a well-studied neuroregenerative factor; however, the degree to which it supports hair formation and skin wound repair is not known. By using a Gfra1 (GDNF family receptor alpha 1) knock-in reporter mouse line, GDNF signaling was found to occur within hair bulge stem cells (BSCs) during the initiation of the hair cycle and early stages of hair formation after depilation. Both recombinant and transgene overexpression of GDNF promoted BSC colony growth, hair formation, and skin repair after wounding through enhanced self-renewal of BSCs and commitment of BSC-derived progenitors into becoming epidermal cells at the injury site. Conditional ablation of Gfra1 among BSCs impaired the onset of the hair cycle, while conditional ablation of the GDNF family member signal transducer, Ret, within BSCs prevented the onset of the hair cycle and depilation-induced anagen development of hair follicles. Our findings reveal that GDNF promotes hair formation and wound repair and that bulge stem cells are critical mediators of both.

Highlights

Hair follicles (HFs) are formed through complex epithelial-mesenchymal interactions
Glial-cell-derived neurotrophic factor (GDNF) initiates the anagen stage of the hair cycle to promote hair formation In order to study the function of GDNF in promoting self-renewal of spermatogonial stem cells, we had generated transgenic mice that overexpressed Gdnf driven by the lysosomal proteinase cathepsin L (Ctsl) gene promoter ( referred to as Tg(CtslGdnf)) within somatic Sertoli cells[20]
Our findings show that GDNF promotes hair formation and cutaneous would healing in mice

Summary

Introduction

Hair follicles (HFs) are formed through complex epithelial-mesenchymal interactions. In mice, the morphogenic period of hair formation ends at approximately postnatal day 14 (P14) when HFs establish a definitive bulge stem cell (BSC) compartment[1,2,3]. During the post-morphogenic period, the lower part of the HF undergoes cyclic transformations of growth, involution, and quiescence. These transitions are termed the anagen, catagen, and telogen stages, respectively[3]. The anagen-to-catagen transition marks the end of the active growth phase by deleting, via apoptosis, the old hair shaft. This positions the remaining dermal papilla (Dp), which serves as an inductive signaling center, within close proximity to BSCs to start a new hair cycle upon activation. During cutaneous wounding of adult skin, a reservoir of BSCs from pre-exiting follicles and/or the interfollicular epithelium (IFE)

Objectives

Methods

Results

Conclusion