Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials

Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic...

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Autores principales: Christof Westenfelder, Zhuma Hu, Ping Zhang, Anna Gooch
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Publicado: Public Library of Science (PLoS) 2021
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spelling oai:doaj.org-article:d094cf18efa24e50be75dbcff79e99932021-11-04T06:49:34ZIntraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials1932-6203https://doaj.org/article/d094cf18efa24e50be75dbcff79e99932021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553138/?tool=EBIhttps://doaj.org/toc/1932-6203Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions. Recently, fetal and induced Pluripotent Stem Cells have been successfully differentiated to generate insulin producing β-like cells that generate euglycemia in diabetic mice. However, their clinical use still depends on anti-rejection drugs or immune-isolating encapsulation systems. We reported recently that allogeneic “Neo-Islets” (NI), 3-D organoids of Mesenchymal Stromal and Islet Cells are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new “endocrine pancreas” delivers islet hormones physiologically into the hepatic portal vein. Furthermore, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. As there remains a critical need for curative therapies of T1DM, we engineered human NIs and tested their ability, after i.p. administration, to reestablish euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice. This diabetes model reproduces, in part, the clinical situation in which recipients of allogeneic biotherapies must take potent anti-rejection drugs that similarly create a life-long immune-compromised status. The present study demonstrates that human NI therapy (2x10e5/kg bw NIs/mouse) of STZ-diabetic NOD/SCID mice (n = 6), compared to controls (n = 6) significantly improved glycemic control, and most importantly, that a second dose given to the initial group normalized blood glucose levels long-term. Conclusion: Despite the limitations of the utilized diabetic NOD/SCID mouse model, the obtained data show that human NIs are curative, an observation that has high translational relevance and significantly supports the planned conduct of clinical trials with human NIs.Christof WestenfelderZhuma HuPing ZhangAnna GoochPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Christof Westenfelder
Zhuma Hu
Ping Zhang
Anna Gooch
Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials
description Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions. Recently, fetal and induced Pluripotent Stem Cells have been successfully differentiated to generate insulin producing β-like cells that generate euglycemia in diabetic mice. However, their clinical use still depends on anti-rejection drugs or immune-isolating encapsulation systems. We reported recently that allogeneic “Neo-Islets” (NI), 3-D organoids of Mesenchymal Stromal and Islet Cells are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new “endocrine pancreas” delivers islet hormones physiologically into the hepatic portal vein. Furthermore, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. As there remains a critical need for curative therapies of T1DM, we engineered human NIs and tested their ability, after i.p. administration, to reestablish euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice. This diabetes model reproduces, in part, the clinical situation in which recipients of allogeneic biotherapies must take potent anti-rejection drugs that similarly create a life-long immune-compromised status. The present study demonstrates that human NI therapy (2x10e5/kg bw NIs/mouse) of STZ-diabetic NOD/SCID mice (n = 6), compared to controls (n = 6) significantly improved glycemic control, and most importantly, that a second dose given to the initial group normalized blood glucose levels long-term. Conclusion: Despite the limitations of the utilized diabetic NOD/SCID mouse model, the obtained data show that human NIs are curative, an observation that has high translational relevance and significantly supports the planned conduct of clinical trials with human NIs.
format article
author Christof Westenfelder
Zhuma Hu
Ping Zhang
Anna Gooch
author_facet Christof Westenfelder
Zhuma Hu
Ping Zhang
Anna Gooch
author_sort Christof Westenfelder
title Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials
title_short Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials
title_full Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials
title_fullStr Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials
title_full_unstemmed Intraperitoneal administration of human “Neo-Islets”, 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials
title_sort intraperitoneal administration of human “neo-islets”, 3-d organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic nod/scid mice: significance for clinical trials
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/d094cf18efa24e50be75dbcff79e9993
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AT zhumahu intraperitonealadministrationofhumanneoislets3dorganoidsofmesenchymalstromalandpancreaticisletcellsnormalizesbloodglucoselevelsinstreptozotocindiabeticnodscidmicesignificanceforclinicaltrials
AT pingzhang intraperitonealadministrationofhumanneoislets3dorganoidsofmesenchymalstromalandpancreaticisletcellsnormalizesbloodglucoselevelsinstreptozotocindiabeticnodscidmicesignificanceforclinicaltrials
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