Exogenous R-Spondin1 Induces Precocious Telogen-to-Anagen Transition in Mouse Hair Follicles.

Na Li,Hui-Shan Zhang,Shuang Liu,Shu Liu,Hai-Bin Wang,Zhi-Li Deng,Qian Zhao,Li-Na Ning,Yu-Jing Cao,Hua-Shan Zhao,Xiao-Hua Lei,En-Kui Duan

doi:10.3390/ijms17040582

Abstract

R-spondin proteins are novel Wnt/β-catenin agonists, which signal through their receptors leucine-rich repeat-containing G-protein coupled receptor (LGR) 4/5/6 and substantially enhance Wnt/β-catenin activity. R-spondins are reported to function in embryonic development. They also play important roles in stem cell functions in adult tissues, such as the intestine and mammary glands, which largely rely on Wnt/β-catenin signaling. However, in the skin epithelium and hair follicles, the information about R-spondins is deficient, although the expressions and functions of their receptors, LGR4/5/6, have already been studied in detail. In the present study, highly-enriched expression of the R-spondin family genes (Rspo1/2/3/4) in the hair follicle dermal papilla is revealed. Expression of Rspo1 in the dermal papilla is specifically and prominently upregulated before anagen entry, and exogenous recombinant R-spondin1 protein injection in mid-telogen leads to precocious anagen entry. Moreover, R-spondin1 activates Wnt/β-catenin signaling in cultured bulge stem cells in vitro, changing their fate determination without altering the cell proliferation. Our pioneering study uncovers a role of R-spondin1 in the activation of cultured hair follicle stem cells and the regulation of hair cycle progression, shedding new light on the governance of Wnt/β-catenin signaling in skin biology and providing helpful clues for future treatment of hair follicle disorders.

Highlights

The Wnt/β-catenin signaling is accepted as the dominant player regulating multiple aspects of skin biology, such as the morphogenesis and patterning of skin epithelium and its appendages, the self-renewal and differentiation of resident stem cells in skin, as well as the functions of numerous differentiated skin cells [1]
R-Spondin1-4 Expression Is Enriched in the Telogen Hair Follicle Dermal Papilla, and R-Spondin1 Expression Is Upregulated before Anagen Entry
The K14+ epidermal cells from the hair follicle outer root sheath showed nuclear green fluorescent protein (GFP) fluorescence and the Lef1+ dermal papilla (DP) was labeled with red fluorescent protein (RFP) fluorescence (Figure 1a)

Summary

Introduction

The Wnt/β-catenin signaling is accepted as the dominant player regulating multiple aspects of skin biology, such as the morphogenesis and patterning of skin epithelium and its appendages, the self-renewal and differentiation of resident stem cells in skin, as well as the functions of numerous differentiated skin cells [1]. The hair cycle is controlled by extensive interactions between the hair follicle epithelial cells and the local dermal cells, especially those in the dermal papilla (DP), an organized structure at the bottom of a hair follicle which is comprised of specialized dermal mesenchymal cells [2,3]. In these complex epithelial-mesenchymal interactions and the entire hair cycle regulation, the Wnt/β-catenin pathway plays diverse and essential roles at different aspects, for example, the transition from telogen to anagen, and the lineage decisions during hair follicle differentiation. In highly-regenerative epithelial tissues such as the intestine and the mammary gland, where the canonical Wnt/β-catenin pathway has a well-established position, R-spondins are found to play especially critical roles, in the tissue development, and in adult stem cell functions [5,10,11,12]

Methods

Results

Conclusion