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Tissue renewal by adult stem cells is regulated by a multitude of cell intrinsic and extrinsic mechanism, which jointly guide decisions between two cell fates - stem cell self-renewal and differentiation. Interestingly, the microenvironment of stem cells, also called the niche, has often a distinct shape.Recent findings by us and others demonstrate that metabolism can influence cell fate. As metabolites can be exchanged between cells, we hypothesize that fate of tissue stem cells is controlled by metabolism running jointly within the surrounding cellular community, and the geometry of the niche facilitates this communal metabolism. Moreover, age-induced changes in tissue architecture may deregulate metabolite sharing and thereby tissue renewal by stem cells.We will first establish the order of metabolic and transcriptional events during fate change. Second, we assess the extent and impact of metabolite sharing by developing methods capable of detecting exchange of metabolites between two cell types. To study the impact of niche geometry, we will develop artificial scaffolds instructing custom niche topology. Finally, we will characterize the tissue geometry alterations during aging, and probe the possibility to promote tissue regeneration by supporting a youthful geometry via apical constriction of cells.Our work challenges the fundamental concept of cell fate, and has the potential to uncover metabolic tools advancing protocols for future cellular therapies.

The rapid advancement of stem cell research creates a foundation for future therapeutic strategies spanning from organ replacements to treatment of diabetes and neurodegenerative disease, and to aging-related frailty and disease. To fully realize the potential of stem cell based strategies, we must first understand the cellular processes critical for stem cell function. We have discovered that metabolism is a potent driver of stem cell fate and that metabolic interventions can guide stem cell function. Subsequently, we have for example succeeded in producing near-mature stem cell derived pancreatic islets, that produce insulin in response to elevated glucose. During the second term, we will focus on illuminating how metabolism controls differentiation of stem cells in a tissue environment, and whether metabolic tools can be used to enhance the maturation of lab-grown pancreatic islets for stem cell based diabetes therapy.