SAT067 Bone Marrow-induced Epithelial-Mesenchymal Transition In Beta Cells

Abstract

Abstract Disclosure: J. Lee: None. Normal cellular function is achieved via regulated cell differentiation cues. Deregulation of these intricately wired processes promotes cellular dysfunction. The pancreatic islet beta cell (β-cell) is a prime example of such integration between optimal cell differentiation and function. Fully differentiated adult β-cells synthesize and secrete insulin. But some express more than one single hormone, and cells containing insulin and glucagon (Ins+:Glu+ cells) are seen during prenatal pancreas development. Interestingly, Ins+:Glu+ cells have been observed in adult islets from diabetic mice or type 2 diabetes (T2D) human cadavers. It is still unclear the origins and relevance of these Ins+:Glu+ cells, and whether this phenomenon is a benefit in the context of severe β-cell stress. But, growing evidence suggests that Ins+:Glu+ cells represent attempts made by the mature β-cell to return to an immature stage with the goal of proliferating and reconstituting depleted β-cell reservoir when faced with a metabolic challenge. In this study, we thus investigated whether adult β-cells undergo epithelial to mesenchymal transition (EMT) that allows β-cells to retrace the developmental steps and attempt β-cell functional recovery. EMT can be induced by many growth factors and cytokines activated when epithelial cells encounter specific signals released by their immediate neighbors. The bone marrow microenvironment can activate EMT in adjacent cells through the secretion of chemokines, cytokines, and growth factors. We postulated bone marrow cells (BMCs) could induce EMT in β-cell. To accomplish this goal, we have developed islet cell and bone marrow cell co-culture conditions. Islets and bone marrow cells obtained from normal chow diet (NCD) and high-fat diet-fed (HFD) mice as well as specimens from non-diabetic and T2D humans are used in co-culture systems. RNA sequencing analysis showed that co-culture pancreatic islet cells with whole bone marrow cells induced the expression of genes relative to mesenchymal cells and suppressed beta cell marker genes like MafA, Ins. Results from immunofluorescence staining analysis also revealed that BMCs promoted mesenchymal phenotype in islet β-cells. We found that cytokines known to induce EMT were secreted in the co-culture media. Mice fed with HFD increased levels of that cytokines in serum compared to NCD. We further confirmed that cytokines secreted by BMCs activated EMT in mouse and human islet β-cells. Blocking of cytokines signaling decreased mesenchymal phenotypes in islet β-cells. Overall, our data suggest that EMT of β-cells is regulated by bone marrow cells via crosstalk between bone marrow cells and pancreatic islets using cytokines. Presentation: Saturday, June 17, 2023