Amphiregulin promotes hair regeneration of skin-derived precursors via the PI3K and MAPK pathways.

Qiumei Lu,Xiaodong Chen,Shuai Wang,Xusheng Wang,Xing Xiao,Zhimeng Fan,Meijian Liao,Weiwei Chu,Yuan Si,Ying Gao,Yu Chen,Deqiang Kong

doi:10.1111/cpr.13106

Abstract

ObjectivesThere are significant clinical challenges associated with alopecia treatment, including poor efficiency of related drugs and insufficient hair follicles (HFs) for transplantation. Skin‐derived precursors (SKPs) exhibit great potential as stem cell‐based therapies for hair regeneration; however, the proliferation and hair‐inducing capacity of SKPs gradually decrease during culturing.Materials and MethodsWe describe a 3D co‐culture system accompanied by kyoto encyclopaedia of genes and genomes and gene ontology enrichment analyses to determine the key factors and pathways that enhance SKP stemness and verified using alkaline phosphatase assays, Ki‐67 staining, HF reconstitution, Western blot and immunofluorescence staining. The upregulated genes were confirmed utilizing corresponding recombinant protein or small‐interfering RNA silencing in vitro, as well as the evaluation of telogen‐to‐anagen transition and HF reconstitution in vivo.ResultsThe 3D co‐culture system revealed that epidermal stem cells and adipose‐derived stem cells enhanced SKP proliferation and HF regeneration capacity by amphiregulin (AREG), with the promoted stemness allowing SKPs to gain an earlier telogen‐to‐anagen transition and high‐efficiency HF reconstitution. By contrast, inhibitors of the phosphoinositide 3‐kinase (PI3K) and mitogen‐activated protein kinase (MAPK) pathways downstream of AREG signalling resulted in diametrically opposite activities.ConclusionsBy exploiting a 3D co‐culture model, we determined that AREG promoted SKP stemness by enhancing both proliferation and hair‐inducing capacity through the PI3K and MAPK pathways. These findings suggest AREG therapy as a potentially promising approach for treating alopecia.

Highlights

Alopecia resulting from various factors that decrease hair follicle (HF) regeneration[1] affects a significant fraction of the world population
By exploiting a 3D co-culture model, we determined that AREG promoted Skin-derived precursors (SKPs) stemness by enhancing both proliferation and hair-inducing capacity through the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways
Hair transplantation is regarded as the gold standard for creating natural-appearing hair in androgenic alopecia (AGA),[7] there is an unavoidable controversy surrounding autologous transplantation owing to the limited source of donor hair, the decreased viability of cells extracted in this time-consuming procedure, and, most importantly, the impermanent outcomes as the disease progresses.[1,3]

Summary

Introduction

Alopecia resulting from various factors that decrease hair follicle (HF) regeneration[1] affects a significant fraction of the world population. Hair transplantation is regarded as the gold standard for creating natural-appearing hair in androgenic alopecia (AGA),[7] there is an unavoidable controversy surrounding autologous transplantation owing to the limited source of donor hair, the decreased viability of cells extracted in this time-consuming procedure, and, most importantly, the impermanent outcomes as the disease progresses.[1,3] Regarding oral medicines, drugs approved by the Food and Drug Administration (FDA), such as finasteride, dutasteride and minoxidil for AGA, vary greatly in efficacy from person to person and provide partial and temporary benefits, as well as side effects.8-11 Such surgical procedures and medications cannot always meet patient satisfaction given the finite sources, unfavourable side effects and partial benefits

Objectives

Discussion

Conclusion