1764-P: Cross Talk between Pancreatic Mesenchymal Stem Cells and Macrophages Facilitates ß-Cell Decompensation in Obesity

Introduction & Objective: Obesity has long been recognized as a significant risk factor for developing type 2 diabetes mellitus (T2DM), the mechanisms triggering β-cell compensation and subsequent decompensation are still not fully understood. Our research has brought to light that in conditions of decompensation, macrophage presence in pancreatic islets is significantly increased while the population of mesenchymal stem cells (MSCs) concurrently decreases, which may reveal the true cause of dynamic change of pancreatic islets.

Methods: Single-cell sequencing methods can comprehensively characterize the diversity of cell types. In this study, we utilized a murine model of T2DM, established by feeding wild-type C57BL/6J mice with a high-fat diet (HFD), combining single-cell sequencing technology to investigate the effects and molecular mechanisms of cell interaction on β-cell decompensation.

Results: Our results show that pancreatic islet macrophages cause TNF-α dependent inhibition of Wnts release in MSCs, which leads to a decrease in β-cell numbers and insulin secretion. We also demonstrated that the loss of macrophages somewhat alleviates obesity-induced insulin resistance, while the injection of fresh MSCs can completely reverse β-cell decompensation. Meanwhile protective measures against HFD-induced β-cell dysfunction in mice were observed following the selective removal of macrophages and the subsequent introduction of MSCs.

Conclusion: These findings underscore the pivotal role of communication between macrophages and MSCs in modulating β-cell adaptive responses and functional impairment in obesity. Elucidating a precise mechanism for the effect of obesity on interaction between macrophages and MSCs will broaden our understanding of the pathophysiological development of diabetes and facilitate the design of better tools for diabetes prevention and treatment.