Skin cell heterogeneity and dynamics during morphogenesis, tissue homeostasis, and regeneration

Abstract: Skin is our protective barrier against various environmental harms. For the skin to fulfill its crucial function, it relies on multiple cell types working in concert; but most importantly it relies on skin-resident epithelial stem cells. These cells ensure an intact barrier through constant replacement of the epidermis and they ensure proper hair production through cyclical regeneration of hair follicles. This combination of constant and cyclical renewal within one tissue makes skin a prime model system for the study of adult tissue stem cells. The overall aim of this thesis was to transcriptionally dissect this well-established model system in a systematic and unbiased way. The majority of data presented in this thesis is based on the combination of single-cell RNA sequencing and in situ stainings of mRNA. This combination allows us to appreciate the genome-wide transcriptional heterogeneity while still being able to place the identified cell populations in their spatial tissue context. In Paper I, the first whole-transcriptome study of skin at the single-cell level, we examined the vectors describing cellular heterogeneity within the epidermal compartment of mouse skin during its resting stage (telogen). In Paper II, we expanded on this analysis by including full-thickness skin during rest (telogen) and growth (anagen). This allowed for an unbiased census of all major cell types contained in the skin, and it furthermore enabled us to study how skin achieves and accommodates hair growth. In Paper III, we studied the role of dermal fibroblasts in early embryonic skin development. We uncovered unexpected heterogeneity among embryonic fibroblasts and explored their supportive functions for skin maturation. Moreover, we identified novel keratinocyte subpopulations and closely analyzed epidermal fate decisions. In Paper IV, we monitored transcriptional adaptations of two distinct epidermal stem cell populations during their contribution to wound healing. This allowed us to answer fundamental questions about stem cell plasticity and the dynamics of cell adaptations following injury. In sum, this thesis uncovers the dynamic and heterogeneous nature of mouse skin during adult tissue homeostasis, embryonic development, and tissue regeneration after injury. Most importantly, we provide new insights into how stem cell identity is shaped and how developmental as well as regenerative processes are orchestrated.

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