Epidermal stem cells ensure that skin homeostasis is maintained. In murine skin, epidermal stem cells cluster at specific niches where, at steady state conditions, they undergo cycles of dormancy and activation. Upon the requirement of cellular replenishment, epidermal stem cells egress the niche and proliferate for a limited number of times to subsequently feed into the differentiated compartment. However, at each round of morphogenesis, only a subset of stem cells becomes active, suggesting that heterogeneous stem cell responsive states coexist within the same niche. Using a circadian clock fluorescent reporter mouse model, we show that the dormant epidermal stem cell niche contains two populations of stem cells at opposite phases of the clock, which are differentially predisposed to respond to niche homeostatic cues. In dormant niches, the core molecular clock circuitry transcriptionally modulates the expression of stem cell regulatory genes to create two coexisting stem cell populations, one predisposed, and one less prone, to activation. Unbalancing this equilibrium of epidermal stem cells, through conditional epidermal deletion of a core clock component, results in a long-term progressive accumulation of non-responsive stem cells, premature impairment of tissue self-renewal, and a significant reduction in the development of squamous cell carcinomas. In addition, we are studying how the clock machinery times epidermal stem cell functions, such as UV response, DNA damage repair, cellular replenishment and differentiation, according to the natural day and night cycles.
We propose that the molecular clock machinery finetunes the spatiotemporal behavior of epidermal stem cells within their niche, and that perturbation of this mechanism affects tissue homeostasis and the predisposition to neoplastic transformation.
Die Cookie-Einstellungen auf dieser Website sind auf "Cookies zulassen" eingestellt, um das beste Surferlebnis zu ermöglichen. Wenn du diese Website ohne Änderung der Cookie-Einstellungen verwendest oder auf "Akzeptieren" klickst, erklärst du sich damit einverstanden.