Membrane sphingolipid composition orchestrating adult stem cell maintenance and fate

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The aim of this project is to understand how lipids, in particular ceramides, control stem cell behaviour and contribute to stem cell aging, and thus to the regenerative capacity of a tissue. Lipids play an essential role in energy homeostasis, membrane mechanics and signalling. Ceramides, synthesized by ceramide synthases (CerS), are the essential building blocks of all cellular membranes and can serve as signalling molecules. The capacity of stem cells to self-renew or differentiate can be attributed to distinct metabolic states, and emerging evidence suggests that lipid metabolism plays a fundamental role in stem cell homeostasis (1,2), but the mechanisms are unclear. Our objective is to identify the molecular and cellular mechanisms by which ceramides control the fate and dynamic behaviour of adult stem cells using the stem cells of the skin epidermis as a paradigm. Our preliminary data indicate that the membrane lipid composition is altered in CerS-deficient and aged stem cells, and we postulate that this change, via altering (mechano)chemical signalling, compromises stem cell renewal and alters lineage fidelity. We furthermore hypothesize that interfering with membrane lipid compositions is a potent mechanism to restore impairments of stem cell function of CerS-deficient and aged stem cells. We will address these hypotheses by: 1. Determining how CerS expression and age control the sphingolipidomes of the epidermis and its stem- and progenitor cells 2. Identifying functional defects of CerS-deficient and aged stem- and progenitor cells and restoring their function ex vivo 3. Deciphering signalling and/ or mechanochemical events leading to reduced stem cell numbers upon CerS-deficiency and ageing This project is central to understand how ceramide-associated metabolic and mechanochemical signals are integrated to control stem cell function and fate within tissues. Understanding these principles are key to understanding how aging alters adult stem cell renewal and fate to drive aging-associated diseases, such as (skin) cancer, fibrosis and impaired wound healing. Exploring the novel role of lipids will further facilitate the development of approaches to enhance stem cell expansion and differentiation in vitro for the use of regenerative medicine. It may, in the long run, also allow tuning stem cell behaviour in vivo, by modulating lipid metabolic pathways pharmacologically or through diet, serving as therapeutic tools for aging-associated diseases.