Role of the Ubiquitin System in Adult Stem Cells

Adult stem cells play fundamental roles in tissue homeostasis and repair as they are able to self-renew and produce all the different cellular types present in that tissue. The renewal of the intestinal epithelium is driven by LGR5-positive stem cells that are situated at the bottom of the intestinal crypt. These cells are associated with terminally differentiated Paneth cells that provide Wnt, Notch and Epidermal Growth Factor signals. Importantly, LGR5-positive stem cells can be isolated and cultured in vitro where they form three-dimensional organotypic structures, termed organoids, which contain crypt-villus structures that recapitulate the native intestinal epithelium. The overall objective of our research is to study the molecular mechanisms controlling stem cell maintenance and differentiation, focusing particularly on the role of ubiquitylation in these processes. The selectivity of ubiquitylation depends on E3 ubiquitin ligases, which are responsible for the specific recognition of the target proteins. We intend to 1) identify ubiquitin ligases that control the maintenance and differentiation of intestinal stem cells, 2) study the molecular mechanisms regulating substrate ubiquitylation in stem cells and 3) employ intestinal organoids for the analysis of the functional significance of ubiquitylation in adult stem cells. Since the high specificity renders ubiquitin ligases prime candidates for drug targets, our work will have implications not only in regenerative medicine but also in personalized medicine and drug discovery.