Signalling by senescent melanocytes hyperactivates hair growth

Abstract

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular cells

“…These observations provide evidence for a pro-angiogenic effect of FOL-026. Earlier experimental and clinical studies have shown that treatment with the FOL-026 analogue FOL-005 as well as osteopontin 4,18 stimulates hair growth but the mechanisms responsible for this effect have been unclear. Yano and coworkers 9 were first to demonstrate that the transition of resting hair follicles into the anagen growth phase is preceded by an increased perifollicular vascularization and that this is activated by an increased expression of VEGF in follicular keratinocytes in the outer root sheath of the hair follicle and FOL-005 has been shown to also accumulate around and affect these cells.…”

Interpretation of the Yak Skin Single-Cell Transcriptome Landscape

“…This means that SPP1 plays an important role in fibroblasts and shows high expression characteristics under matrix activation, which further promotes the high expression of fibrosis genes [89]. By using Tyr-NrasQ61K; Spp1−/−mice, researchers found that SPP1 loss-of-function mutations are sufficient to reverse the static hair cycle in the skin of congenital nevus and that SPP1 can induce new hair growth [90]. Periodic hair growth and dormancy are complex processes regulated by a variety of internal and external factors, and SPP1 is a key mediator, which indicates that high expression of SPP1 in fibroblasts may play an important role in regulating hair cycle and wound repair.…”

Review: Are moles senescent?

“…Other groups who induced Braf V600E in similar but older mice found that the sparser clones grew larger and then did show evidence of senescence, more like typical human nevi (Dhomen et al, 2009;Kohli et al, 2022;Wang et al, 2023). Ruiz-Vega et al (2020) proposed that their conclusion on nonsenescence could also be applied to human nevi, on two specific grounds.…”