Human Fetal Scalp Dermal Papilla Enriched Genes and the Role of R-Spondin-1 in the Restoration of Hair Neogenesis in Adult Mouse Cells.

Erin L Weber,Cheng-Ming Chuong,Mingxing Lei,Yung-Chih Lai,Ting-Xin Jiang

doi:10.3389/fcell.2020.583434

Abstract

Much remains unknown about the regulatory networks which govern the dermal papilla’s (DP) ability to induce hair follicle neogenesis, a capacity which decreases greatly with age. To further define the core genes which characterize the DP cell and to identify pathways prominent in DP cells with greater hair inductive capacity, comparative transcriptome analyses of human fetal and adult dermal follicular cells were performed. 121 genes were significantly upregulated in fetal DP cells in comparison to both fetal dermal sheath cup (DSC) cells and interfollicular dermal (IFD) populations. Comparison of the set of enriched human fetal DP genes with human adult DP, newborn mouse DP, and embryonic mouse dermal condensation (DC) cells revealed differences in the expression of Wnt/β-catenin, Shh, FGF, BMP, and Notch signaling pathways. We chose R-spondin-1, a Wnt agonist, for functional verification and show that exogenous administration restores hair follicle neogenesis from adult mouse cells in skin reconstitution assays. To explore upstream regulators of fetal DP gene expression, we identified twenty-nine transcription factors which are upregulated in human fetal DP cells compared to adult DP cells. Of these, seven transcription factor binding motifs were significantly enriched in the candidate promoter regions of genes differentially expressed between fetal and adult DP cells, suggesting a potential role in the regulatory network which confers the fetal DP phenotype and a possible relationship to the induction of follicle neogenesis.

Highlights

The dermal papilla (DP), though distinctly different from the dermal condensation (DC) and primarily responsible for cyclical regeneration of the mature follicle, retains the follicle-inducing property of its DC progenitor
To identify core genes shared by DP cells across different organisms, ages, and follicle types, we compared the fetal scalp DP transcriptome with human adult DP, newborn mouse DP, and embryonic mouse DC datasets
We identified key transcription factor binding motifs in promoter regions upstream of genes differentially expressed in fetal compared to adult DP cells to determine potential upstream regulators and a foundation for multiple downstream signaling networks

Summary

INTRODUCTION

The DP, though distinctly different from the DC and primarily responsible for cyclical regeneration of the mature follicle, retains the follicle-inducing property of its DC progenitor. If existing adult DP cells could be expanded in culture and reprogrammed to possess higher inductive capacity akin to the fetal DC or DP, transplantation of such cells may offer a new treatment for androgenetic alopecia or skin injury (Chueh et al, 2013; Higgins and Christiano, 2014) With this in mind, we investigated the gene expression profile of the human fetal DP, a structure which is more anatomically distinct than the DC, and, through comparative transcriptomics, determined differences in gene expression between fetal and adult DP cells. In this analysis of human fetal DP cells, the R-spondins, a family of Wnt agonists, were differentially upregulated and the exogenous administration of R-spondin-1 rescued hair follicle neogenesis in adult mouse reconstitution assays

MATERIALS AND METHODS

RESULTS

DISCUSSION