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

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.

A human prenatal skin cell atlas reveals immune cell regulation of skin morphogenesis

“…These self-renewing dermal cells are located within the dermal sheath, a structure of layered connective tissue surrounding the hair follicle 50 . We did not detect a distinct cluster of dermal sheath cells in 7-16 PCW prenatal skin, although this has been identified in a previous single cell analysis of human fetal scalp from 16 and 17 PCW 51 . This is consistent with the earlier development of hair follicles in the scalp compared to trunk skin 6,31 .…”

Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities

“…Wnt3a and β-catenin in hair stromal cells accelerate the hair follicle cycle and promote hair regeneration by activating the Wnt/β-catenin signalling pathway. 186 – 189 In addition, the transcription factor Twist1 upregulates the expression of downstream target genes of TCF4, such as HGF, VEGF, and IGF-1, by forming complexes with TCF4 and β-catenin, promoting the proliferation of dermal papilla cells and inducing hair follicle regeneration. 190 …”

Exploiting the Receptor-Binding Domains of R-Spondin 1 to Target Leucine-Rich Repeat-Containin G-Coupled Protein Receptor 5-Expressing Stem Cells in Ovarian Cancer

“…However, this produces no adverse clinical consequences. Repeated large daily doses produce a proliferative response in the stem cells of the jejunum (Zhou et al, 2013;Sun et al, 2021), liver (Sun et al, 2021) and skin (Weber et al, 2020) but this too is well-tolerated. Indeed, RSPO1 facilitates recovery from both radiation-and chemically-induced enteritis (Zhao et al, 2007;Zhao et al, 2009;Zhou et al, 2013).…”