Transcriptional Profiling of the Adult Hair Follicle Mesenchyme Reveals R-spondin as a Novel Regulator of Dermal Progenitor Function

Abstract

The adult hair follicle (HF) undergoes successive regeneration driven by resident epithelial stem cells and neighboring mesenchyme. Recent work described the existence of HF dermal stem cells (hfDSCs), but the genetic regulation of hfDSCs and their daughter cell lineages in HF regeneration remains unknown. Here we prospectively isolate functionally distinct mesenchymal compartment in the HF (dermal cup [DC; includes hfDSCs] and dermal papilla) and define the transcriptional programs involved in hfDSC function and acquisition of divergent mesenchymal fates. From this, we demonstrate cross-compartment mesenchymal signaling within the HF niche, whereby DP-derived R-spondins act to stimulate proliferation of both hfDSCs and epithelial progenitors during HF regeneration. Our findings describe unique transcriptional programs that underlie the functional heterogeneity among specialized fibroblasts within the adult HF and identify a novel regulator of mesenchymal progenitor function during tissue regeneration.

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

“…R-spondins are Wnt activators which function through both the canonical and non-canonical Wnt/βcatenin pathways. All four R-spondins are expressed in the mouse anagen DP and injection of Rspo1, Rspo2, and Rspo3 into adult mouse dermis induces rapid telogen to anagen transition and activation of epidermal follicular stem cells (Li et al, 2016;Smith et al, 2016;Hagner et al, 2020;Harshuk-Shabso et al, 2020). Much less is known about the role of R-spondins in hair follicle development.…”

“…In the absence of these four factors, adult mouse cells are unable to self-organize into any structure resembling a hair follicle. As there is known redundancy in the function of R-spondin genes (Neufeld et al, 2012;Hagner et al, 2020) and Rspo1 rescues adult hair follicle neogenesis, Rspo3 is also a promising candidate for the recovery of inductivity in human adult DP cells. In in vitro colony-forming assays with human dermal progenitor cells, addition of RSPO2/3 increased proliferation and the number and size of progenitor cell colonies (Hagner et al, 2020).…”

The dermal sheath: An emerging component of the hair follicle stem cell niche

“…The DS cup expresses the DS marker αSMA and lacks the DP marker LEF1, [ 37 ] and recent transcriptomic analyses of the murine pelage DS, DS cup and DP further reveal the distinct molecular signatures of these mesenchymal compartments. [ 38–40 ] Thus, the DS and its cup are contiguous with, but morphologically and molecularly distinct from, the DP.…”

“…A comprehensive understanding of the DS niche will likely be the first step of developing and improving DS cell‐based therapeutics, since recapitulating the in vivo niche when culturing DP is crucial to maintaining its hair‐inductive activity, for example by culturing DP as spheroids [ 96 ] or in the presence of Wnt and BMP ligands. [ 14,15 ] For DS, culturing in the presence of PDGF [ 86 ] or Wnt‐enhancing RSPO ligands [ 38 ] might augment the expansion of DS in culture while retaining HF‐inductive capacity. In the future, combining bulk and single‐cell transcriptomics will reveal candidate genes and signalling pathways that confer DS hair inductivity—prime for exploitation in cell‐based therapeutics—as well as the full scope of DS heterogeneity.…”

Current stem cells technologies used in medicine

“…R-spondins may initiate synchronous activation of epithelial and mesenchymal hair follicle regeneration. So secreting R-spondin activates the proliferation of hair follicle dermal stem cells and is an important modulator of stem cell function and tissue regeneration in a variety of organs [4].…”