TY - JOUR
T1 - Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes
AU - Yu, Ming
AU - Agarwal, Divyansh
AU - Korutla, Laxminarayana
AU - May, Catherine L.
AU - Wang, Wei
AU - Griffith, Negin Noorchashm
AU - Hering, Bernhard J.
AU - Kaestner, Klaus H.
AU - Velazquez, Omaida C.
AU - Markmann, James F.
AU - Vallabhajosyula, Prashanth
AU - Liu, Chengyang
AU - Naji, Ali
N1 - Funding Information:
We thank S. Rostami, B. Koeberlein and G. Quinn for their valuable assistance in data collection and development of animal models. We thank Y. J. Wang for assistance with the islet β-cell BrdU staining experiments. We also acknowledge the support of J. Schug, Technical Director of the Next-Generation Sequencing Core at the University of Pennsylvania, for exosome sequencing analysis. We thank members of the Pancreatic Islet Isolation Team at the University of Pennsylvania (Y. Li, Z. Min and X. Zuo). D.A. thanks the Blavatnik Family Foundation for the Graduate Student Fellowship he received during his MD/PhD training. We also thank the National Institutes of Health for award nos. NIH/ NIDDK DK070430, NIH/NIAID AI-102430 and NIH/NIDDK UC4–112217 (HPAP), and the NIDDK IIDP for the grant (Beckman Research Center, no. 10028044) awarded to A.N.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - The intrahepatic milieu is inhospitable to intraportal islet allografts1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.
AB - The intrahepatic milieu is inhospitable to intraportal islet allografts1–3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet–islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.
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U2 - 10.1038/s42255-020-0269-7
DO - 10.1038/s42255-020-0269-7
M3 - Article
C2 - 32895576
AN - SCOPUS:85090317452
VL - 2
SP - 1013
EP - 1020
JO - Nature Metabolism
JF - Nature Metabolism
SN - 2522-5812
IS - 10
ER -
