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

Author:

Gou Wenyu12,Hua Wei1,Swaby Lindsay1,Cui Wanxing3,Green Erica1,Morgan Katherine A.1,Strange Charlie4,Wang Hongjun125ORCID

Affiliation:

1. 1Department of Surgery, Medical University of South Carolina, Charleston, SC

2. 2Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC

3. 3Georgetown University, Washington, DC

4. 4Department of Medicine, Medical University of South Carolina, Charleston, SC

5. 5Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC

Abstract

Islet/β-cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic coinfusion of human α-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more 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-γ–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 cotransplanted 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 cotransplanted 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 β-cell survival during islet/β-cell transplantation for the treatment of type 1 diabetes or other diseases.

Funder

Department of Veterans Affairs

Hollings Cancer Center, Medical University of South Carolina

National Institutes of Health

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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