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)
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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.
Item Type: | Articles |
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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. |
Status: | Published |
Refereed: | Yes |
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: | 1946-6234 |
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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