Postgraduate Researcher University of California, Los Angeles (UCLA), California, United States
Abstract: The various functions of stem cells during development, regeneration and in homeostasis are determined by their trajectory towards differentiation, self-renewal, or quiescence, and disrupting these paths can lead to a variety of diseases. While transcription factors and chromatin regulators are known to regulate pluripotency and cell fate, increasing evidence shows that extrinsic factors like the nutrient environment and the extracellular matrix (ECM) can regulate stem cell functions. The ECM is a complex network of proteins that surrounds the cells, provides structural support and transduces mechanical and biochemical signals to influence cell behavior, including proliferation, migration, and differentiation. Despite its importance, the role of ECM in regulating stem cell function remains inadequately explored. Our work aims to address this gap by investigating how nutrient-driven changes in metabolism influence ECM composition and stem cell reprogramming. Specifically, we focus on Vitamin C (VitC), an essential nutrient that enhances pluripotency induction and is commonly used in iPSC culture media. Using metabolomic approaches, we show that VitC rapidly enhances glucose flux towards Pentose phosphate pathway (PPP) and Hexosamine biosynthesis pathway (HBP) early in reprogramming. Further, VitC addition leads to depletion of intracellular Col1 and ColIV and enhances ECM deposition. VitC derived ECM can regulate cell physiology and enhance reprogramming efficiency. Altogether, we propose that VitC modulates ECM deposition through its effect on cellular metabolism, particularly by enhancing glycosylation pathways necessary for glycosaminoglycan and collagen production. This, in turn, alters ECM composition and promotes iPSC generation. These findings provide novel insights into how metabolism and ECM interact to regulate stem cell fate transitions. Our work also advances the understanding of ECM’s role in stem cell function, with broad implications for improving stem cell therapies, tissue engineering, and regenerative medicine, as well as addressing diseases linked to ECM dysregulation.
Funding Source: CIRM-BSCRC Postdoctoral Fellowship, BSCRC Innovation Award
