Cell adhesion and tissue dynamics in the skin

Project Summary Our global objective is to develop a molecular understanding of how during development a population of stem cells (SCs) are set aside to produce, maintain and regenerate our tissues. As our longstanding AR27883 research on skin has shown, our basic science approach has led to advances in regenerative medicine and our understanding of human syndromes. Our skin epidermis is our body's barrier to the outside world: it must keep harmful microbes out and retain essential body fluids. Our current research centers on how emerging tissue SCs sense and interact with their surroundings (cells, signals and mechanical forces) not only to achieve a balance of proliferation and differentiation, but also to eliminate underperforming tissue cells as they arise. Understanding how healthy epidermal SCs arise and how they perform their duties is prerequisite to unraveling how cellular organization goes awry in inflammatory disorders and cancers of the skin. During skin development, stratified epidermis (and its hair follicle appendages) forms from a single layer of unspecified progenitors. As morphogenesis proceeds, resident epidermal SCs are set aside so that in adult skin, these self-renewing progenitors maintain and repair the skin's barrier. To what extent do self and non-self epidermal SC neighbors, and the mechanical forces they generate, participate in regulating SC behavior during normal homeostasis? What is the molecular nature of this communication circuitry that balances epidermal growth and differentiation? In the next 5 years, we'll: (1). Spatially map the temporal dynamics of cells and their transcriptomes as embryonic skin progenitors interact with newly emerging self and/or non-self neighbors, which together shape the niches that allow progenitors to behave as mature SCs with defined tasks. (2). Identify key signaling inputs that orchestrate the continual flux of epidermal progenitors and differentiating progeny that maintains and rejuvenates the body's barrier. (3). Elucidate how epidermis eliminates poorly performing cells for the sake of tissue fitness. (4). Elucidate how key signaling pathways and transcriptional events drive different regional mechanical forces during skin development and contribute to distinct morphologies and tissue functions. We'll apply the knowledge gained to determine how deviations in stem cell crosstalk with neighbors (`niche') lead to disease. To meet our aims, we and our collaborators developed unprecedented tools to a) spatiotemporally landscape gene expression across the skin, b) interrogate how mechanical forces impact tissue biology and c) track and characterize SCs as they sense and eliminate aberrant neighbors to preserve tissue fitness. While promising for regenerative medicine, adult tissue stem cells are long-lived and can also accumulate mutations that compromise tissue fitness and enhance cancer susceptibility. By unraveling how healthy SCs eliminate aberrantly performing cells, and yet over time, allow phenotypically silent oncogenic clonal diversity to accumulate, we aim to advance therapeutics to halt cancers before they appear. Our work on how mechanical forces impact SC behavior will be equally key in understanding how aggressive cancers arise.