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bioRxiv · 10.1101/2025.08.04.668458

Human and mouse regenerative macrophages enhance beta cell survival, function, and proliferation

Monajemi, M.·Craciun, A.·Huang, Q.·Dai, L.·Mojibian, M.·Crome, S.·Verchere, C. B.·Levings, M. K.
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Abstract

Aims/hypothesisType 1 diabetes is an autoimmune disease caused by immune-mediated destruction of insulin-producing pancreatic beta cells. Interestingly, individuals with long-standing type 1 diabetes have residual beta cells, suggesting the existence of regenerative mechanisms that help maintain beta cell survival. Islet-resident macrophages have an important role in type 1 diabetes, and during disease progression can adopt a tissue-regenerating phenotype which may support beta cells. However, the specific roles of macrophages in beta cell survival, function, and proliferation remains poorly defined. This study aimed to elucidate how different macrophage subtypes influence beta cell survival, function, and proliferation. MethodsMouse and human islets were isolated from the pancreas and co-cultured in vitro with macrophages. To investigate whether macrophages enhance beta cell survival and function, beta cell apoptosis was measured using flow cytometry, and insulin secretion was assessed using a glucose-stimulated insulin secretion assay. We also examined whether macrophages further increased beta cell proliferation in the presence of harmine, a DYRK1A inhibitor. Finally, we evaluated the effect of islet co-culture on macrophage phenotype by flow cytometry and cytokine secretion analysis. ResultsWe found that regenerative, but not pro-inflammatory, macrophages enhanced beta cell survival and function through mechanisms that did not require direct cell contact. Direct contact between macrophages and islets further promoted a regenerative phenotype in macrophages, characterized by increased CD206 expression and secretion of anti-inflammatory factors. Additionally, regenerative macrophages promoted beta cell proliferation in the presence of harmine. ConclusionsOur findings demonstrate that regenerative macrophages support pancreatic beta cell survival, function, and proliferation. Harnessing the regenerative properties of macrophages could offer a novel strategy to promote beta cell survival and function, thereby improving outcomes for individuals with type 1 diabetes. Research in ContextWhat is already known about this subject? O_LIMacrophages are the predominant resident immune cells within pancreatic islets in non-diabetic individuals; they contribute to tissue homeostasis and immune surveillance. C_LIO_LIDepending on their activation state, macrophages can exert either beneficial (pro-regenerative) or harmful (pro-inflammatory) effects on beta cell function. C_LI What is the key question? O_LIHow do different macrophage subtypes regulate islet survival, regeneration, and function? C_LI What are the new findings? O_LICo-culturing mouse or human islets with regenerative macrophages enhanced beta cell survival and function. When added in the presence of a DYRK1A inhibitor (harmine), they also promoted beta cell proliferation. C_LIO_LIRegenerative macrophage-derived factors promoted mouse islet function via a contact independent mechanism. C_LIO_LIMouse islets enhanced the regenerative phenotype of macrophages. C_LI How might this impact on clinical practice in the foreseeable future? O_LILeveraging the regenerative potential of macrophages represents a novel therapeutic approach to enhance beta cells, ultimately improving outcomes for individuals with type 1 diabetes. C_LI

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Monajemi, M., Craciun, A., Huang, Q., Dai, L., Mojibian, M., Crome, S., Verchere, C. B., Levings, M. K.. 2025-08-05. Human and mouse regenerative macrophages enhance beta cell survival, function, and proliferation. https://doi.org/10.1101/2025.08.04.668458

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