Antagonistic stem cell fates under stress govern decisions between hair greying and melanoma [RNA-seq]
The incidence of diseases, including cancer, increases with age. While age-associated diseases with stem cell exhaustion are potentially antagonistic to cancer development1, the relationship between those is still largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately govern the antagonism between poliosis (hair graying) and melanoma. We found that McSCs undergo senescence-associated differentiation (seno-differentiation) in response to DNA double strand breaks (DSBs) such as by ionizing radiation (IR) and ageing upon their activation for self-renewal, leading to their depletion and resultant hair graying at the cost of cancer protection. RNA-seq and functional analysis of the skin exposed to different types of genotoxic stress revealed that activation of the p53-p21 axis and TBK1 pathway by DSBs within McSCs causes their depletion. Comparative analysis of the young vs. aged stem cell niche identified the KIT ligand (KITL/SCF) as a master niche factor for McSC self-renewal. Strikingly, co-exposure of the irradiated skin to carcinogens rescued hair graying by augmenting the secretory phenotype of niche cells to repress McSC seno-differentiation through the dual activation of KIT signaling and arachidonic acid pathway in McSCs. Collectively, our data provide concrete evidence for the phenotypic trade-off between ageing and cancer based on the niche. Overall design: Gene expression profiling of FACS-purified hair follicle stem cells/hair germ from young and old mice in telogen and early anagen (n=3).