A single mouse skin cell can switch from being a stem cell to a committed skin cell in a matter of hours, and researchers now plan to watch that transition happen in real time. Tissues like skin are constantly renewing themselves, but scientists have mostly studied stem cells by looking at snapshots of large populations—missing the fast, individual decisions each cell makes. This project will track those decisions as they occur, using biosensors that glow when a cell commits to a particular fate, and single-cell genetic tools that reveal which cells are stem cells and which are not. If successful, this work will explain how skin maintains itself day to day, and how it repairs itself after injury—for example, when sebaceous duct cells revert to stem cells to heal a wound. It will also show what goes wrong when these transitions are disrupted, which could clarify the earliest steps in skin inflammation and cancer. This is fundamental science: it will not produce a treatment tomorrow, but understanding the normal choreography of cell states is the necessary foundation for knowing how that choreography breaks down in disease.
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Our knowledge of tissue stem cells is based on end-point analysis of cell populations. However, to understand tissue dynamics it is essential to analyse changes in the state of individual cells that occur within minutes or hours. I therefore propose to characterise newly identified mammalian epidermal cell state transitions and the mechanisms that control them. I will first examine how an autoregulatory protein phosphatase network controls commitment. Using an ERK MAPK biosensor I will examine temporal and spatial control of commitment; whether different signals trigger a common commitment state; and the relationship between commitment and lineage selection. Second, I will study two stem cell subpopulations, identified by single cell transcriptomics, which underlie a common epidermal lineage. By examining transitions between these cells I will determine whether the stem cells are interconvertible or have a hierarchical relationship, and whether they are autonomous or competitive. Thirdly, I will characterise injury-induced dedifferentiation by elucidating the transcriptional trajectory of Gata6-positive sebaceous duct cells as they revert to stem cells. Finally, I will explore how perturbation of these transitions contributes to epidermal inflammation and cancer. This research will provide new insights into the role of dynamic cell state transitions in tissue homeostasis and disease.
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