Abstract

The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes, including hair greying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate tracking in mice revealed that McSCs undergo cellular senescence-coupled differentiation (seno-differentiation) in response to DNA double-strand breaks, resulting in their selective depletion and hair greying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in cells harbouring double-strand breaks, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones—expansion versus exhaustion—cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.

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