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.
Subject(s)
Hair , Melanocytes , Signal Transduction , Animals , Mice , Hair/cytology , Hair/growth & development , Hair Follicle/cytology , Hair Follicle/physiology , Hyaluronan Receptors/metabolism , Melanocytes/cytology , Melanocytes/metabolism , Nevus/metabolism , Nevus/pathology , Osteopontin/metabolism , Stem Cells/cytologyABSTRACT
Epidermis can grow its surface by activating mitotic division in basal stem cells. In a recent issue of Nature,Chan et al. (2022) show that under high demand for new skin, differentiated epidermal cells in zebrafish divide without DNA synthesis, forming cells in the new surface with reduced and abnormal genomes.
Subject(s)
Keratinocytes , Zebrafish , Animals , Cell Differentiation , Cell Division , Epidermal Cells , Epidermis/metabolism , Keratinocytes/metabolism , Skin/metabolismABSTRACT
Wounds in mammals commonly heal by scarring but retain latent capacity to regenerate. In this issue of Developmental Cell, Brewer, Nelson et al. reveal that heightened ability of spiny mice to regenerate after injury is attributed to molecular changes in the Hippo-YAP (yes-associated protein) pathway that protect wound fibroblasts from a persistent contractile state.
