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

Forbes, S. et al. (2020) Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization. Science Translational Medicine, 12(526), eaan5907. (doi: 10.1126/scitranslmed.aan5907) (PMID:31941825)

208841.pdf - Accepted Version



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.

Item Type:Articles
Additional Information:Chief Scientist Office (ETM/325 and TCS/17/31) to S.F. and J.D.M.C., Diabetes UK (BDA 13/0004682) to S.F., Wellcome Trust–University of Edinburgh Institutional Strategic Support Fund to S.F. and J.D.M.C., and the Edinburgh and Lothians Health Foundation Award to S.F. R.N.C. and N.M.M. were funded by a Wellcome Trust Investigator Award (100981/Z/13/Z to N.M.M.). We acknowledge NHS Scotland, the UK Islet Transplant Consortium, which has received funding from Diabetes UK (BDA 06/0003362), Diabetes Research and Wellness Foundation, and the Juvenile Diabetes Research Foundation.
Glasgow Author(s) Enlighten ID:Burgoyne, Paul and Campbell, Dr John and THIRLWELL, Kayleigh and Graham, Professor Gerard
Authors: Forbes, S., Bond, A. R., Thirlwell, K. L., Burgoyne, P., Samuel, K., Noble, J., Borthwick, G., Colligan, D., McGowan, N. W. A., Lewis, P. S., Fraser, A. R., Mountford, J. C., Carter, R. N., Morton, N. M., Turner, M. L., Graham, G., and Campbell, J. D.M.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Science Translational Medicine 12(526):eaan5907
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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