Research ArticleISLET TRANSPLANTATION

Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization

See allHide authors and affiliations

Science Translational Medicine  15 Jan 2020:
Vol. 12, Issue 526, eaan5907
DOI: 10.1126/scitranslmed.aan5907

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Improving islet transplantation

Pancreatic islet transplantation can stabilize blood glucose in individuals with type 1 diabetes; however, transplant function decreases occur over time, and suitable donor islet availability remains limited. Forbes et al. investigated the supportive effects of cotransplanting islets and perivascular mesenchymal stromal cells isolated from human umbilical cords (HUCPVCs). The HUCPVCs inhibited T cells and expressed proregenerative and immunoregulatory markers in vitro and increased islet vascularization in vivo. Cotransplanting human islets and HUCPVCs under the kidney capsule or via the hepatic portal vein improved control of blood glucose in diabetic immunodeficient and immunocompetent mouse models for up to 16 weeks. Results suggest that HUCPVCs could help improve long-term islet transplant function.

Abstract

Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.

View Full Text

Stay Connected to Science Translational Medicine