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

Islet/beta-cell transplantation offers great hope for patients with type 1 diabetes. We assessed themechanisms of how intrahepatic coinfusion of human alpha-1 antitrypsin (hAAT)engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantlymore islets in the livers bearing islets cotransplanted with hAAT-MSCs compared with islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-gamma-inducedM1-likemacrophages 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 cotransplanted withhAAT-MSCsas identified bymultiplex 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 cotransplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategymay be used to enhance beta-cell survival during islet/beta-cell transplantation for the treatment of type 1 diabetes or other diseases.

Automated summary

Transplantation of human alpha-1 antitrypsin-engineered mesenchymal stromal cells improves survival of human islet grafts posttransplantation by inhibiting macrophage migration and shifting macrophages to a protective state that favors islet survival.