Dysfunction of Hair Follicle Mesenchymal Progenitors Contributes to Age-Associated Hair Loss

Abstract

Skin aging is accompanied by hair loss due to impairments in hair follicle (HF) epithelial progenitor cells and their mesenchymal niche. This inductive mesenchyme, called dermal papilla (DP), undergoes progressive cell loss and eventual miniaturization that contributes to HF pathogenesis. Using laser ablation and fate mapping, we show that HF dermal stem cells (hfDSCs) reconstitute the damaged DP and maintain hair growth, suggesting that hfDSC dysfunction may trigger degeneration of the inductive niche. Fate mapping over 24 months revealed progressive hfDSC depletion, and in vivo clonal analysis of aged hfDSCs showed impaired selfrenewal and biased differentiation. Single-cell RNA-seq confirmed hfDSCs as a central precursor, giving rise to divergent mesenchymal trajectories. In aged skin, hfDSCs exhibited senescent-like characteristics, and senescence-associated secretory phenotypes were identified in the aging HF mesenchyme. These results clarify fibroblast dynamics within the HF and suggest that progressive dysfunction within the mesenchymal progenitor pool contributes to age-related hair loss.

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

“…Recent lineage‐tracing studies uncovered bipotent hfDSCs that are able to self‐renew and reconstitute the entire DS and contribute to the DP over multiple adult hair cycles. [ 37,39 ] Single‐cell transcriptomics and lineage trajectory analyses of the mesenchyme support the earlier described bipotent state of hfDSCs, [ 37 ] which can give rise to both DS and DP. [ 39 ]…”

“…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][39][40] Thus, the DS and its cup are contiguous with, but morphologically and molecularly distinct from, the DP.…”

Using WGCNA (weighted gene co-expression network analysis) to identify the hub genes of skin hair follicle development in fetus stage of Inner Mongolia cashmere goat

“…The fetal development of primary and secondary hair follicles has been less well studied, and studies of fetal skin and hair follicle development have largely considered the occurrence of primary and secondary hair follicles (fetal period 45-65 days). However, there have been no reports on the maintenance of hair follicle structure and skin hair follicle homeostasis by epithelial cells and fibroblasts during the development and maturation of the primary and secondary hair follicles (115-135 days), even though the stability of the epithelial cells and fibroblasts has been shown to be a key requirement for the hair follicle to enter the hair cycle and to maintain the normal structure of the hair follicle in other mammals [2][3][4][5][6][7].…”

Single‐cell transcriptomic analysis of small and large wounds reveals the distinct spatial organization of regenerative fibroblasts

“…Furthermore, we present two additional experiments that independently show similar results from a reanalysis of flow-sorted alpha-SMACreERT2-RosaeYFP+ve hair follicle mesenchyme from uninjured skin ( Figure S3). 26 This additional explanation highlights the need for additional work to understand reporter gene expression in lineage tracing experiments with droplet-based scRNA-seq studies.…”