Polycomb repressive complex 2 in adult hair follicle stem cells is dispensable for hair regeneration

Hair follicle stem cells (HFSCs) are multipotent cells that cycle through quiescence and activation to continuously fuel the production of hair follicles. Prior genome mapping studies had shown that tri-methylation of histone H3 at lysine 27 (H3K27me3), the chromatin mark mediated by Polycomb Repressive Complex 2 (PRC2), is dynamic between quiescent and activated HFSCs, suggesting that transcriptional changes associated with H3K27me3 might be critical for proper HFSC function. However, functional in vivo studies elucidating the role of PRC2 in adult HFSCs are lacking. In this study, by using in vivo loss-of-function studies we show that, surprisingly, PRC2 plays a non-instructive role in adult HFSCs and loss of PRC2 in HFSCs does not lead to loss of HFSC quiescence or changes in cell identity. Interestingly, RNA-seq and immunofluorescence analyses of PRC2-null quiescent HFSCs revealed upregulation of genes associated with activated state of HFSCs. Altogether, our findings show that transcriptional program under PRC2 regulation is dispensable for maintaining HFSC quiescence and hair regeneration.

Emerging Role of Dermal White Adipose Tissue in Modulating Hair Follicle Development During Aging

Hair follicle stem cells are extensively reprogrammed by the aging process, manifesting as diminished self-renewal and delayed responsiveness to activating cues, orchestrated by both intrinsic microenvironmental and extrinsic macroenvironmental regulators. Dermal white adipose tissue (dWAT) is one of the peripheral tissues directly adjacent to hair follicles (HFs) and acts as a critical macroenvironmental niche of HF. dWAT directly contributes to HF aging by paracrine signal secretion. However, the altered interrelationship between dWAT and HF with aging has not been thoroughly understood. Here, through microdissection, we separated dWAT from the skin of aged mice (18 months) and young mice (2 months) in telogen and depilation-induced anagen for transcriptome comparing. Notably, compared with young dWAT, aberrant inflammatory regulators were recapitulated in aging dWAT in telogen, including substantial overexpressed inflammatory cytokines, matrix metalloproteinases, and prostaglandin members. Nonetheless, with anagen initiation, inflammation programs were mostly abolished in aging dWAT, and instead of which, impaired collagen biosynthesis, angiogenesis, and melanin synthesis were identified. Furthermore, we confirmed the inhibitory effect on hair growth of CXCL1, one of the most significantly upregulated inflammation cytokines in aging dWAT. Besides this, we also identified the under-expressed genes related to Wnt signaling fibroblast growth factor family members and increased BMP signaling in aging dWAT, further unraveling the emerging role of dWAT in aging HFs malfunction. Finally, we proved that relieving inflammation of aging dWAT by injecting high-level veratric acid stimulated HF regenerative behavior in aged mice. Concomitantly, significantly decreased TNF-a, CCL2, IL-5, CSF2, and increased IL10 in dWAT was identified. Overall, the results elaborated on the complex physiological cycling changes of dWAT during aging, providing a basis for the potential regulatory effect of dWAT on aging HFs.

Mechanotransductive Differentiation of Hair Follicle Stem Cells Derived from Aged Eyelid Skin into Corneal Endothelial-Like Cells

Corneal endothelial insufficiency is one of the leading causes of blindness. The main contemporary treatment for corneal blindness is endothelial keratoplasty, which, however, is unsatisfactory as a medical therapy due to the lack of donor corneas and graft rejection. Therefore, autologous stem cell-based corneal endothelial tissue substitutes may be a promising alternative to conventional grafts in the future. To address the age of most patients suffering from corneal endothelial deficiencies, we investigated the presence and potential of hair-derived stem cells from older tissue donors. Our studies revealed the presence of pluripotency- and neural crest-associated markers in tissue sections from blepharoplasty patients aged 50 to 80 years. In vitro outgrowths from eyelid hair follicles on collagen-coated tissue culture plates revealed a weak decrease in stem-cell potency. In contrast, cells within the spheres that spontaneously formed from the adherent cell layer retained full stem-cell potency and could be differentiated into cells of the ecto- meso and endodermal lineages. Although these highly potent hair follicle derived stem cells (HFSC) were only very slightly expandable, they were able to recognize the biomimicry of the Descemet’s-like topography and differentiate into corneal endothelial-like cells. In conclusion, HFSCs derived from epidermal skin of eyelid biopsies are a promising cell source to provide autologous corneal endothelial replacement for any age group of patients. Graphical Abstract