Tu154 - Evidence for a Role of Pro-regenerative Macrophages in Enhancing Beta Cell Survival, Proliferation, and Function

Jessica Huang – Department of Surgery, University of British Columbia – BC Children’s Hospital Research Institute; C. Bruce Verchere – Co-Principal investigator, Department of Surgery, University of British Columbia, BC Children’s Hospital Research Institute; Megan Levings – Principal investigator, Department of Surgery, University of British Columbia, BC Children’s Hospital Research Institute

Abstract Text: Type 1 diabetes (T1D) is a chronic condition arising from a loss of immune tolerance to insulin-producing beta cells, leading to immune cell-mediated beta cell destruction. Our previous research revealed that in diabetic mice islet-resident macrophages shift towards a tissue-regenerating phenotype, characterized by reduced expression of inflammatory cytokines compared to healthy mice. This observation led us to hypothesize that macrophages with a tissue-regenerating phenotype could play a role in promoting beta cell survival and regeneration.

We polarized bone marrow-derived macrophages (BMDMs) from mice into a pro-regenerative (M2-like) phenotype through stimulation with IL-4 and IL-13. Co-culture of 100 Bl/6 mouse islets (intact or dispersed) with 100,000 M2-like macrophages for 6 days through either direct or indirect co-culture systems led to a significant (25%, p< 0.05) increase in beta cell survival, as measured by CytoCalcien fluorescence intensity. Additionally, direct co-culture of dispersed or intact mouse islets with M2-like macrophages for 72-hours resulted in elevated beta cell proliferation (range 0.08 to 2.83%), assessed through flow cytometry measuring EdU+ cells within the insulin+ cell gate. Beta cell function, assessed by glucose-stimulated insulin secretion, also improved (10.7 pM vs 44.8 pM, p< 0.05) following both direct and indirect co-culture of intact mouse islets with M2-like macrophages for 72-hours.

These findings suggest that pro-regenerative (M2-like) macrophages enhance beta cell survival, proliferation and function through secreted factors. Future studies aim to better understand the mechanistic basis for these effects and explore macrophage-mediated islet regeneration using in-vivo transplantation models.