Epidermal stem cells in physiological tissue regeneration, wound healing and cancer

Abstract: The mammalian skin is a versatile organ that protects from external harm, regulates the body temperature, and provides the touch sensation. Its epithelium, the epidermis, forms several highly regenerative structures as the hair follicle (HF), the sebaceous gland (SG), and the interfollicular epidermis (IFE). Lineage tracing experiments in mice have demonstrated that several basal cell populations in the IFE and HF have the capacity to renew the epidermis during homeostasis, and also contribute to wound healing and cancer formation. However, clear insights distinguishing the different stem cell populations and defining their exact spatio-temporal patterns of contribution were lacking. Expression of Lgr5 marks stem cells located in the HF bulge and hair germ. We used lineage tracing of Lgr5-expressing (Lgr5+) cells in mice to investigate how wound healing affects the capacity of epidermal stem cells to initiate skin cancer. Induction of basal cell carcinoma (BCC) through activation of Hedgehog signalling in the entire basal layer confirmed that wounding strongly increases the incidence and severity of BCC-like lesions. Targeting the oncogenic mutation to Lgr5+ cells revealed that transformed HF cells are able to leave their natural environment and establish tumours in the IFE in response to wounding. Thus, wounding activates HF stem cells to expand and migrate to unaffected tissue areas, thereby augmenting BCC development. Since it was discovered that Lgr6 is another epidermal stem cell marker, we set out to explore the role of Lgr6+ stem cells during epidermal homeostasis. Detailed analysis of the lineagetracing pattern of the Lgr6+ cells populations in the isthmus, SG, and IFE disclosed that these resident Lgr6+ populations independently maintain their respective compartment. The mode of tissue renewal displayed by all three Lgr6+ cell populations was in accordance with a stochastic division of one type of progenitor cell. These results highlight that stochastic stem cell renewal is relevant in many types of rapidly proliferating epithelia. We further investigated the susceptibility of the different epidermal compartments harbouring Lgr6+ stem cells towards BCC initiation and evaluated the influence of the microenvironment on tumour formation. Knockout of Ptch1 in Lgr6+ cells resulted in highly accelerated BCC development within the HF isthmus and the touch dome niches in the IFE. The touch dome and the isthmus are both associated with cutaneous nerve fibres, and show several morphological and molecular features that are highly similar to BCC. This demonstrates that these two niches promote the response of the epithelial cells to the oncogenic stimulus. In summary, tracking the fate of Lgr5- and Lgr6-expressing epidermal stem cells during homeostasis, wound healing and early cancer formation shed light on the similarities and differences between distinct stem cell populations in the skin. The results illustrate how stem cell renewal is achieved, elucidate the early steps of skin cancer development, and underline the influence of the microenvironment on the behaviour of tissue stem cells.

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