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Stem Cell Therapy Improves Human Islet Graft Survival in Mice via Regulation of Macrophages

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posted on 2022-09-09, 20:14 authored by Wenyu Gou, Wei Hua, Lindsay Swaby, Wanxing Cui, Erica Green, Katherine Morgan, Charlie Strange, Hongjun Wang

Islet/b cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic co-infusion of human alpha-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improve survival of human islet grafts post-transplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more islets in the livers bearing islets co-transplanted with hAAT-MSCs compared to islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-g-induced M1-like macrophages while promoting IL-4-induced M2-like macrophages. In vivo, this translated to significantly reduced CD11c+ and F4/80+ cells and increased CD206+ cells around islets co-transplanted with hAAT-MSCs as identified by multiplex immunofluorescence staining. Recipient-derived F4/80+and CD11b+ macrophages were mainly present in the periphery of an islet, while CD11c+ and CD206+ cells appeared inside an islet. hAAT-MSCs inhibited macrophage migration and skewed the M1-like phenotype toward an M2 phenotype both in vitro and in vivo, which may have favored islet survival. These data provide evidence that hAAT-MSCs co-transplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategy may be used to enhance b cell survival during islet/b cell transplantation for the treatment of type 1 diabetes or other diseases.

Funding

This study was supported in part by the National Institutes of Health (DK105183, DK 120394 and DK118529, and DK125464) and the Department of Veterans Affairs (VA-ORD BLR&D Merit I01BX004536). This study is partially supported by the Translational Science Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313)

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