Grant: Project Grant

Pluripotent stem cells (PSCs) have the special ability to "expand" - make copies of themselves - and give rise to all cell types of the body. Since their discovery over 40 years ago, PSCs have opened the door to producing cell therapies by transplanting lab-grown cells into the body to restore damaged function. To meet growing clinical demand, we are challenged with the task of growing billions of PSCs for cell therapy production. However, we and others have shown that lab-grown PSCs, like their embryo-resident counterparts, compete with and aggressively eliminate one another. These cellular battles shape their growth and impact our ability to robustly engineer PSCs for therapeutic use. Competition between PSCs is a newly discovered phenomenon and the rules of battle are not yet understood. Here, we will explore the molecular mechanisms that govern cell competition. To do this, we leverage our catalogue of competing mouse PSCs, which are known to engage in contact-mediated killing in a dish. While previous studies point to mitochondrial function as providing a key advantage for winners in competition, the molecular changes that lead losers to perish remain unknown. To probe this question, we will use established approaches (mass spectrometry) and cutting-edge synthetic biology tools ("Ribo-STAMP" and genetic circuits) to track molecular changes during PSC battle. This work will provide a window into multiple layers of the molecular map of cell competition - transcription, translation, and protein abundance - that is only made possible by recent technological advances. As PSC-derived cell therapies are an area of strategic investment for Canada's biotechnology sector, this project provides mechanistic insights that inform our ability to grow and manipulate PSCs. Our datasets will serve as the first molecular blueprints for cell competition, allowing us to uncover the rules that govern hidden cellular battles in PSC culture so that we can better control them.