Cell Competition & Fitness Sensing Mechanisms in Skin

Stem cells are the building blocks that give rise to all our tissues and organs. Stem cells also allow us to regenerate new, healthy tissue as we age, and to repair tissues that are damaged. The health of our tissues thus critically depends on the health of our stem cells; if our stem cells are damaged, the consequences for tissue and organ function can be fatal. Cell competition is a quality control mechanism that acts in stem cells to detect and eliminate sub-optimal stem cells. Similar to Darwinian selection mechanisms, during cell competition, the most fit stem cells are selected for, and cooperate to eliminate less fit and/or damaged stem cells so they do not survive long term in the tissue, where they may have the potential to cause disease. Cell competition is hypothesized to support ongoing tissue function in many different organs but the molecular mechanisms of cell competition are almost completely unknown. My proposal therefore aims to bridge this knowledge gap. In particular, we focus on four key questions: 1- What makes one cell more fit than its neighbour? 2- How is fitness sensed between neighbouring cells? 3- How are less fit cells eliminated from tissues without disrupting tissue function? 4- How do cell competition mechanisms adjust during a tissue injury? To answer these questions, we focus on mammalian skin. Skin is a particularly interesting place to study cell competition because the stem cells in our skin are constantly subject to potentially damage-inducing influences from the environment. These include radiation from the sun, chemicals in the environment, or mechanical damage. I have developed a genetically-tractable system to induce and study cell competition mechanisms in the skin that allows us to follow the growth and survival of single stem cells, and to interrogate their molecular and cellular features. Using this system, together with cutting edge techniques in microscopy, genomics, and wound-healing models, we will gain unprecedented insight into how tissues fine-tune their cellular composition to be comprised of only the fittest stem cells. Our results will shed light on how our tissues maintain health over our long life times and furthermore, how stem cells are able to mobilize robust repair responses after injury. These insights are likely to have broad-reaching implications for our understanding of many diseases, including cancer, that might arise when cell competition processes fail.