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Buemi A, Mourad NI, Bouzin C, Devresse A, Hoton D, Daumerie A, Zech F, Darius T, Kanaan N, Gianello P, Mourad M. Exploring Preservation Modalities in a Split Human Pancreas Model to Investigate the Effect on the Islet Isolation Outcomes. Transplant Direct 2024; 10:e1654. [PMID: 38881744 PMCID: PMC11177812 DOI: 10.1097/txd.0000000000001654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/13/2024] [Accepted: 03/15/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND In islet transplantation, the use of dynamic hypothermic preservation techniques is a current challenge. This study compares the efficacy of 3 pancreas preservation methods: static cold storage, hypothermic machine perfusion (HMP), and oxygenated HMP. METHODS A standardized human pancreas split model was employed using discarded organs from both donation after brain death (n = 15) and donation after circulatory death (DCD) (n = 9) donors. The pancreas head was preserved using static cold storage (control group), whereas the tail was preserved using the 3 different methods (study group). Data on donor characteristics, pancreas histology, isolation outcomes, and functional tests of isolated islets were collected. RESULTS Insulin secretory function evaluated by calculating stimulation indices and total amount of secreted insulin during high glucose stimulation (area under the curve) through dynamic perifusion experiments was similar across all paired groups from both DCD and donation after brain death donors. In our hands, islet yield (IEQ/g) from the pancreas tails used as study groups was higher than that of the pancreas heads as expected although this difference did not always reach statistical significance because of great variability probably due to suboptimal quality of organs released for research purposes. Moreover, islets from DCD organs had greater purity than controls (P ≤ 0.01) in the HMP study group. Furthermore, our investigation revealed no significant differences in pancreas histology, oxidative stress markers, and apoptosis indicators. CONCLUSIONS For the first time, a comparative analysis was conducted, using a split model, to assess the effects of various preservation methods on islets derived from pancreas donors. Nevertheless, no discernible variances were observed in terms of islet functionality, histological attributes, or isolation efficacy. Further investigations are needed to validate these findings for clinical application.
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Affiliation(s)
- Antoine Buemi
- Surgery and Abdominal Transplantation Division, Department of Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Nizar I. Mourad
- Pôle de Chirurgie Expérimentale et Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Caroline Bouzin
- IREC Imaging Platform (2IP, RRID:SCR_023378), Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Arnaud Devresse
- Nephrology Division, Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Delphine Hoton
- Department of Anatomical Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Aurelie Daumerie
- IREC Imaging Platform (2IP, RRID:SCR_023378), Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Francis Zech
- Pôle de Chirurgie Expérimentale et Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Tom Darius
- Surgery and Abdominal Transplantation Division, Department of Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Nada Kanaan
- Nephrology Division, Department of Internal Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Pierre Gianello
- Pôle de Chirurgie Expérimentale et Transplantation, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Michel Mourad
- Surgery and Abdominal Transplantation Division, Department of Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
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2
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Brandhorst D, Brandhorst H, Acreman S, Johnson PRV. The ischaemic preconditioning paradox and its implications for islet isolation from heart-beating and non heart-beating donors. Sci Rep 2022; 12:19321. [PMID: 36369239 PMCID: PMC9652462 DOI: 10.1038/s41598-022-23862-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022] Open
Abstract
The impact of ischaemia can severely damage procured donor organs for transplantation. The pancreas, and pancreatic islets in particular, is one of the most sensitive tissues towards hypoxia. The present study was aimed to assess the effect of hypoxic preconditioning (HP) performed ex-vivo in islets isolated from heart-beating donor (HBD) and non heart-beating donor (NHBD) rats. After HP purified islets were cultured for 24 h in hypoxia followed by islet characterisation. Post-culture islet yields were significantly lower in sham-treated NHBD than in HBD. This difference was reduced when NHBD islets were preconditioned. Similar results were observed regarding viability, apoptosis and in vitro function. Reactive oxygen species generation after hypoxic culture was significantly enhanced in sham-treated NHBD than in HBD islets. Again, this difference could be diminished through HP. qRT-PCR revealed that HP decreases pro-apoptotic genes but increases HIF-1 and VEGF. However, the extent of reduction and augmentation was always substantially higher in preconditioned NHBD than in HBD islets. Our findings indicate a lower benefit of HBD islets from HP than NHBD islets. The ischaemic preconditioning paradox suggests that HP should be primarily applied to islets from marginal donors. This observation needs evaluation in human islets.
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Affiliation(s)
- Daniel Brandhorst
- Research Group for Islet Transplantation, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
| | - Heide Brandhorst
- Research Group for Islet Transplantation, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Samuel Acreman
- Research Group for Islet Transplantation, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Paul R V Johnson
- Research Group for Islet Transplantation, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
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3
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Gloyn AL, Ibberson M, Marchetti P, Powers AC, Rorsman P, Sander M, Solimena M. Every islet matters: improving the impact of human islet research. Nat Metab 2022; 4:970-977. [PMID: 35953581 PMCID: PMC11135339 DOI: 10.1038/s42255-022-00607-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 06/14/2022] [Indexed: 11/10/2022]
Abstract
Detailed characterization of human pancreatic islets is key to elucidating the pathophysiology of all forms of diabetes, especially type 2 diabetes. However, access to human pancreatic islets is limited. Pancreatic tissue for islet retrieval can be obtained from brain-dead organ donors or from individuals undergoing pancreatectomy, often referred to as 'living donors'. Different protocols for human islet procurement can substantially impact islet function. This variability, coupled with heterogeneity between individuals and islets, results in analytical challenges to separate genuine disease pathology or differences between human donors from experimental noise. There are currently no international guidelines for human donor phenotyping, islet procurement and functional characterization. This lack of standardization means that substantial investments from multiple international efforts towards improved understanding of diabetes pathology cannot be fully leveraged. In this Perspective, we overview the status of the field of human islet research, highlight the challenges and propose actions that could accelerate research progress and increase understanding of type 2 diabetes to slow its pandemic spreading.
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Affiliation(s)
- Anna L Gloyn
- Department of Pediatrics, Division of Endocrinology & Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
| | - Mark Ibberson
- Vital-IT, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alvin C Powers
- Vanderbilt University Medical Center, Nashville, TN, USA
- VA Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Metabolic Physiology Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden
| | - Maike Sander
- Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, San Diego, CA, USA
| | - Michele Solimena
- Department of Molecular Diabetology, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
- Paul Langerhans Institute Dresden and German Center for Diabetes Resaerch (DZD e.V.), Helmholtz Center Munich at University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
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4
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De Paep DL, Van Hulle F, Ling Z, Vanhoeij M, Hilbrands R, Distelmans W, Gillard P, Keymeulen B, Pipeleers D, Jacobs-Tulleneers-Thevissen D. Utility of Islet Cell Preparations From Donor Pancreases After Euthanasia. Cell Transplant 2022; 31:9636897221096160. [PMID: 35583214 PMCID: PMC9125111 DOI: 10.1177/09636897221096160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Patients fulfilling criteria for euthanasia can choose to donate their organs after circulatory death [donors after euthanasia (DCD V)]. This study assesses the outcome of islet cell isolation from DCD V pancreases. A procedure for DCD V procurement provided 13 pancreases preserved in Institut Georges Lopez-1 preservation solution and following acirculatory warm ischemia time under 10 minutes. Islet cell isolation outcomes are compared with those from reference donors after brain death (DBD, n = 234) and a cohort of donors after controlled circulatory death (DCD III, n = 29) procured under the same conditions. Islet cell isolation from DCD V organs resulted in better in vitro outcome than for selected DCD III or reference DBD organs. A 50% higher average beta cell number before and after culture and a higher average beta cell purity (35% vs 24% and 25%) was observed, which led to more frequent selection for our clinical protocol (77% of isolates vs 50%). The functional capacity of a DCD V islet cell preparation was illustrated by its in vivo effect following intraportal transplantation in a type 1 diabetes patient: injection of 2 million beta cells/kg body weight (1,900 IEQ/kg body weight) at 39% insulin purity resulted in an implant with functional beta cell mass that represented 30% of that in non-diabetic controls. In conclusion, this study describes procurement and preservation conditions for donor organs after euthanasia, which allow preparation of cultured islet cells, that more frequently meet criteria for clinical use than those from DBD or DCD III organs.
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Affiliation(s)
- Diedert L De Paep
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.,Beta Cell Bank, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.,Department of Surgery, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Freya Van Hulle
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Zhidong Ling
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.,Beta Cell Bank, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Marian Vanhoeij
- Department of Surgery, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Robert Hilbrands
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.,Diabetes Clinic, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Wim Distelmans
- Supportive and Palliative Care, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Pieter Gillard
- Diabetes Clinic, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.,Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | - Bart Keymeulen
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.,Diabetes Clinic, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Daniel Pipeleers
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Daniel Jacobs-Tulleneers-Thevissen
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.,Beta Cell Bank, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.,Department of Surgery, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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5
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Doppenberg JB, Nijhoff MF, Engelse MA, de Koning EJP. Clinical use of donation after circulatory death pancreas for islet transplantation. Am J Transplant 2021; 21:3077-3087. [PMID: 33565712 PMCID: PMC8518956 DOI: 10.1111/ajt.16533] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 01/17/2021] [Accepted: 02/03/2021] [Indexed: 01/25/2023]
Abstract
Due to a shortage of donation after brain death (DBD) organs, donation after circulatory death (DCD) is increasingly performed. In the field of islet transplantation, there is uncertainty regarding the suitability of DCD pancreas in terms of islet yield and function after islet isolation. The aim of this study was to investigate the potential use of DCD pancreas for islet transplantation. Islet isolation procedures from 126 category 3 DCD and 258 DBD pancreas were performed in a 9-year period. Islet yield after isolation was significantly lower for DCD compared to DBD pancreas (395 515 islet equivalents [IEQ] and 480 017 IEQ, respectively; p = .003). The decrease in IEQ during 2 days of culture was not different between the two groups. Warm ischemia time was not related to DCD islet yield. In vitro insulin secretion after a glucose challenge was similar between DCD and DBD islets. After islet transplantation, DCD islet graft recipients had similar graft function (AUC C-peptide) during mixed meal tolerance tests and Igls score compared to DBD graft recipients. In conclusion, DCD islets can be considered for clinical islet transplantation.
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Affiliation(s)
- Jason B. Doppenberg
- Department of Internal MedicineLeiden University Medical CenterLeidenthe Netherlands
- Transplantation CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Michiel F. Nijhoff
- Transplantation CenterLeiden University Medical CenterLeidenthe Netherlands
- Department of EndocrinologyLeiden University Medical CenterLeidenthe Netherlands
| | - Marten A. Engelse
- Department of Internal MedicineLeiden University Medical CenterLeidenthe Netherlands
- Transplantation CenterLeiden University Medical CenterLeidenthe Netherlands
| | - Eelco J. P. de Koning
- Department of Internal MedicineLeiden University Medical CenterLeidenthe Netherlands
- Transplantation CenterLeiden University Medical CenterLeidenthe Netherlands
- Department of EndocrinologyLeiden University Medical CenterLeidenthe Netherlands
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6
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Iworima DG, Rieck S, Kieffer TJ. Process parameter development for the scaled generation of stem cell-derived pancreatic endocrine cells. Stem Cells Transl Med 2021; 10:1459-1469. [PMID: 34387389 PMCID: PMC8550703 DOI: 10.1002/sctm.21-0161] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/28/2021] [Accepted: 07/05/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetes is a debilitating disease characterized by high blood glucose levels. The global prevalence of this disease has been projected to reach 700 million adults by the year 2045. Type 1 diabetes represents about 10% of the reported cases of diabetes. Although islet transplantation can be a highly effective method to treat type 1 diabetes, its widespread application is limited by the paucity of cadaveric donor islets. The use of pluripotent stem cells as an unlimited cell source to generate insulin‐producing cells for implant is a promising alternative for treating diabetes. However, to be clinically relevant, it is necessary to manufacture these stem cell‐derived cells at sufficient scales. Significant advances have been made in differentiation protocols used to generate stem cell‐derived cells capable of reversing diabetes in animal models and for testing in clinical trials. We discuss the potential of both stem cell‐derived pancreatic progenitors and more matured insulin‐producing cells to treat diabetes. We discuss the need for rigorous bioprocess parameter optimization and identify some critical process parameters and strategies that may influence the critical quality attributes of the cells with the goal of facilitating scalable manufacturing of human pluripotent stem cell‐derived pancreatic endocrine cells.
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Affiliation(s)
- Diepiriye G Iworima
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Timothy J Kieffer
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
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7
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Soetedjo AAP, Lee JM, Lau HH, Goh GL, An J, Koh Y, Yeong WY, Teo AKK. Tissue engineering and 3D printing of bioartificial pancreas for regenerative medicine in diabetes. Trends Endocrinol Metab 2021; 32:609-622. [PMID: 34154916 DOI: 10.1016/j.tem.2021.05.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/08/2023]
Abstract
Diabetes is a severe chronic disease worldwide. In various types of diabetes, the pancreatic beta cells fail to secrete sufficient insulin, at some point, to regulate blood glucose levels. Therefore, the replacement of dysfunctional pancreas, islets of Langerhans, or even the insulin-secreting beta cells facilitates physiological regulation of blood glucose levels. However, the current lack of sufficient donor human islets for cell replacement therapy precludes a routine and absolute cure for most of the existing diabetes cases globally. It is envisioned that tissue engineering of a bioartificial pancreas will revolutionize regenerative medicine and the treatment of diabetes. In this review, we discuss the anatomy and physiology of the pancreas, and identify the clinical considerations for engineering a bioartificial pancreas. Subsequently, we dissect the bioengineering problem based on the design of the device, the biomaterial used, and the cells involved. Last but not least, we highlight current tissue engineering challenges and explore potential directions for future work.
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Affiliation(s)
- Andreas Alvin Purnomo Soetedjo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore
| | - Jia Min Lee
- School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Hwee Hui Lau
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore
| | - Guo Liang Goh
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Jia An
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Yexin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Wai Yee Yeong
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; Department of Biochemistry and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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8
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Doppenberg JB, Leemkuil M, Engelse MA, Krikke C, de Koning EJP, Leuvenink HGD. Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation: a prospective feasibility study. Transpl Int 2021; 34:1397-1407. [PMID: 34036616 PMCID: PMC8456912 DOI: 10.1111/tri.13927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/14/2021] [Accepted: 05/16/2021] [Indexed: 11/28/2022]
Abstract
Due to an increasing scarcity of pancreases with optimal donor characteristics, islet isolation centers utilize pancreases from extended criteria donors, such as from donation after circulatory death (DCD) donors, which are particularly susceptible to prolonged cold ischemia time (CIT). We hypothesized that hypothermic machine perfusion (HMP) can safely increase CIT. Five human DCD pancreases were subjected to 6 h of oxygenated HMP. Perfusion parameters, apoptosis, and edema were measured prior to islet isolation. Five human DBD pancreases were evaluated after static cold storage (SCS). Islet viability, and in vitro and in vivo functionality in diabetic mice were analyzed. Islets were isolated from HMP pancreases after 13.4 h [12.9–14.5] CIT and after 9.2 h [6.5–12.5] CIT from SCS pancreases. Histological analysis of the pancreatic tissue showed that HMP did not induce edema nor apoptosis. Islets maintained >90% viable during culture, and an appropriate in vitro and in vivo function in mice was demonstrated after HMP. The current study design does not permit to demonstrate that oxygenated HMP allows for cold ischemia extension; however, the successful isolation of functional islets from discarded human DCD pancreases after performing 6 h of oxygenated HMP indicates that oxygenated HMP may be a useful technology for better preservation of pancreases.
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Affiliation(s)
- Jason B Doppenberg
- Transplantation Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Marjolein Leemkuil
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Marten A Engelse
- Transplantation Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Christina Krikke
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Eelco J P de Koning
- Transplantation Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
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9
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De Paep DL, Van Hulle F, Ling Z, Vanhoeij M, Pirenne J, Keymeulen B, Pipeleers D, Jacobs-Tulleneers-Thevissen D. Lower beta cell yield from donor pancreases after controlled circulatory death prevented by shortening acirculatory warm ischemia time and by using IGL-1 cold preservation solution. PLoS One 2021; 16:e0251055. [PMID: 33939760 PMCID: PMC8092795 DOI: 10.1371/journal.pone.0251055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/19/2021] [Indexed: 02/07/2023] Open
Abstract
Organs from donors after controlled circulatory death (DCD III) exhibit a higher risk for graft dysfunction due to an initial period of warm ischemia. This procurement condition can also affect the yield of beta cells in islet isolates from donor pancreases, and hence their use for transplantation. The present study uses data collected and generated by our Beta Cell Bank to compare the number of beta cells in isolates from DCD III (n = 141) with that from donors after brain death (DBD, n = 609), before and after culture, and examines the influence of donor and procurement variables. Beta cell number per DCD III-organ was significantly lower (58 x 106 versus 84 x 106 beta cells per DBD-organ; p < 0.001) but their purity (24% insulin positive cells) and insulin content (17 μg / 106 beta cells in DCD III-organs versus 19 μg / 106 beta cells in DBD-organs) were similar. Beta cell number correlated negatively with duration of acirculatory warm ischemia time above 10 min; for shorter acirculatory warm ischemia time, DCD III-organs did not exhibit a lower beta cell yield (74 x 106 beta cells). Use of Institut Georges Lopez-1 cold preservation solution instead of University of Wisconsin solution or histidine-tryptophan-ketoglutarate also protected against the loss in beta cell yield from DCD III-organs (86 x 106 for IGL-1 versus 54 x 106 and 65 x 106 beta cells respectively, p = 0.042). Multivariate analysis indicates that both limitation of acirculatory warm ischemia time and use of IGL-1 prevent the reduced beta cell yield in islet cell isolates from DCD III-organs.
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Affiliation(s)
- Diedert L. De Paep
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Diabetes Clinic, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- Department of Surgery, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Freya Van Hulle
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Diabetes Clinic, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Zhidong Ling
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Diabetes Clinic, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Marian Vanhoeij
- Department of Surgery, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Jacques Pirenne
- Department of Abdominal Transplantation and Transplantation Coordination, University Hospitals Leuven, Leuven, Belgium
| | - Bart Keymeulen
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Diabetes Clinic, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Daniel Pipeleers
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Diabetes Clinic, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Daniel Jacobs-Tulleneers-Thevissen
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Diabetes Clinic, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- Department of Surgery, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- * E-mail:
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10
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The Effects of Using Pancreases Obtained from Brain-Dead Donors for Clinical Islet Transplantation in Japan. J Clin Med 2019; 8:jcm8091430. [PMID: 31510059 PMCID: PMC6780198 DOI: 10.3390/jcm8091430] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/03/2019] [Accepted: 09/05/2019] [Indexed: 01/09/2023] Open
Abstract
Background: The pool of brain-dead donors (BDDs) was increased with the revision to the relevant law in 2010, and islet transplantation from BDDs was started in 2013. The present study assessed the influence of using pancreases from BDDs on islet transplantation in Japan. Methods: The donor information registered with the secretariat of islet transplants from 2012 was reviewed, and the results of 86 clinical islet isolations performed in Japan between 2003 and 2018 with non-heart-beating donors (NHBDs) (n = 71) and BDDs (n = 15) were investigated. Results: The number of cases for which donor information was registered with the secretariat of islet transplants increased to 1.84 cases/month from 2013 to 2018 in comparison to 1.44/month in 2012, when only NHBDs were used. The median pancreatic islet yield was 275,550 IEQ (Islet equivalents) in the NHBD group but 362,700 in the BDD group, which amounted to a statistically significant difference (p = 0.02). As a result, 38/71 cases (53.5%) were achieved successful islet isolation (>5000 IEQ per recipient weight (kg)) was achieved in 38/71 cases (53.5%) in the NHBD group, and 12/15 cases (80.0%) in the BDD group; thus, the rate of successful islet transplantation was higher in the BDD group. Conclusion: The use of pancreases from BDDs has increased the overall number of cases for which donor information is registered with the secretariat of islet transplants and has improved the performance of islet isolation, thereby increasing the probability of successfully achieving islet transplantation.
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11
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Rickels MR, Robertson RP. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions. Endocr Rev 2019; 40:631-668. [PMID: 30541144 PMCID: PMC6424003 DOI: 10.1210/er.2018-00154] [Citation(s) in RCA: 193] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/26/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
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Affiliation(s)
- Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - R Paul Robertson
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- Pacific Northwest Diabetes Research Institute, Seattle, Washington
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12
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Zhu H, Zhang X, He Y, Yu L, Lü Y, Pan K, Wang B, Chen G. [Research progress on the donor cell sources of pancreatic islet transplantation for treatment of diabetes mellitus]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:104-111. [PMID: 29806374 PMCID: PMC8414200 DOI: 10.7507/1002-1892.201707049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 12/13/2017] [Indexed: 11/03/2022]
Abstract
Objective To summarize the research progress on the source and selection of donor cells in the field of islet replacement therapy for diabetes mellitus. Methods Domestic and abroad literature concerning islet replacement therapy for diabetes mellitus, as well as donor source and donor selection was reviewed and analyzed thoroughly. Results The shortage of donor supply is still a major obstacle for the widely clinical application of pancreatic islet transplantation (PIT). Currently, in addition to the progress on the allogeneic/autologous donor islet supply, some remarkable achievements have been also attained in the application of xenogeneic islet (from pig donor), as well as islet like cells derived from stem cells and islet cell line, potentially enlarging the source of implantable cells. Conclusion Adequate and suitable donor cell supply is an essential prerequisite for widely clinical application of PIT therapy for type 1 diabetes mellitus (T1DM). Further perfection of organ donation system, together with development of immune-tolerance induction, gene and bioengineering technology etc. will possibly solve the problem of donor cell shortage and provide a basis for clinical application of cellular replacement therapy for T1DM.
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Affiliation(s)
- Haitao Zhu
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China;Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Xiaoge Zhang
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China
| | - Yayi He
- Department of Endocrinology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Liang Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Yi Lü
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China;Research Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Kaili Pan
- Department of Pediatrics (No. 2 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China
| | - Bo Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China;Department of Endocrinology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061,
| | - Guoqiang Chen
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061,
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13
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Abstract
OBJECTIVES Attaining high-quality RNA from the tissues or organs of deceased donors used for research can be challenging due to physiological and logistical considerations. In this investigation, METHODS: RNA Integrity Number (RIN) was determined in pancreatic samples from 236 organ donors and used to define high (≥6.5) and low (≤4.5) quality RNAs. Logistic regression was used to evaluate the potential effects of novel or established organ and donor factors on RIN. RESULTS Univariate analysis revealed donor cause of death (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.15-0.77; P = 0.01), prolonged tissue storage before RNA extraction (OR, 0.65; 95% CI, 0.52-0.79; P < 0.01), pancreas region sampled (multiple comparisons, P < 0.01), and sample type (OR, 0.32; 95% CI, 0.15-0.67; P < 0.01) negatively influenced outcome. Conversely, duration of final hospitalization (OR, 3.95; 95% CI, 1.59-10.37; P < 0.01) and sample collection protocol (OR, 8.48; 95% CI, 3.96-19.30; P < 0.01) positively impacted outcome. Islet RNA obtained via laser capture microdissection improved RIN when compared with total pancreatic RNA from the same donor (ΔRIN = 1.3; 95% CI, 0.6-2.0; P < 0.01). CONCLUSIONS A multivariable model demonstrates that autopsy-free and biopsy-free human pancreata received, processed, and preserved at a single center, using optimized procedures, from organ donors dying of anoxia with normal lipase levels increase the odds of obtaining high-quality RNA.
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14
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Bruni A, Pepper AR, Gala-Lopez B, Pawlick R, Abualhassan N, Crapo JD, Piganelli JD, Shapiro AMJ. A novel redox-active metalloporphyrin reduces reactive oxygen species and inflammatory markers but does not improve marginal mass engraftment in a murine donation after circulatory death islet transplantation model. Islets 2016; 8:e1190058. [PMID: 27220256 PMCID: PMC4987021 DOI: 10.1080/19382014.2016.1190058] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Islet transplantation is a highly effective treatment for stabilizing glycemic control for select patients with type-1 diabetes. Despite improvements to clinical transplantation, single-donor transplant success has been hard to achieve routinely, necessitating increasing demands on viable organ availability. Donation after circulatory death (DCD) may be an alternative option to increase organ availability however, these organs tend to be more compromised. The use of metalloporphyrin anti-inflammatory and antioxidant (MnP) compounds previously demonstrated improved in vivo islet function in preclinical islet transplantation. However, the administration of MnP (BMX-001) in a DCD islet isolation and transplantation model has yet to be established. In this study, murine donors were subjected to a 15-min warm ischemic (WI) period prior to isolation and culture with or without MnP. Subsequent to one-hour culture, islets were assessed for in vitro viability and in vivo function. A 15-minute WI period significantly reduced islet yield, regardless of MnP-treatment relative to yields from standard isolation. MnP-treated islets did not improve islet viability compared to DCD islets alone. MnP-treatment did significantly reduce the presence of extracellular reactive oxygen species (ROS) (p < 0 .05). Marginal, syngeneic islets (200 islets) transplanted under the renal capsule exhibited similar in vivo outcomes regardless of WI or MnP-treatment. DCD islet grafts harvested 7 d post-transplant exhibited sustained TNF-α and IL-10, while MnP-treated islet-bearing grafts demonstrated reduced IL-10 levels. Taken together, 15-minute WI in murine islet isolation significantly impairs islet yield. DCD islets do indeed demonstrate in vivo function, though MnP therapy was unable to improve viability and engraftment outcomes.
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Affiliation(s)
- Antonio Bruni
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Andrew R. Pepper
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Boris Gala-Lopez
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Rena Pawlick
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Nasser Abualhassan
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - James D. Crapo
- Department of Medicine, National Jewish Health, Denver, CO, USA, and BioMimetix JV, LLC, Englewood, CO, USA
| | - Jon D. Piganelli
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- BioMimetix JV, LLC, Englewood, CO, USA
| | - A. M. James Shapiro
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- CONTACT A.M. James Shapiro, MD, PhD, Professor, Director of Clinical Islet and Living Donor Liver Transplant Programs, Canada Research Chair in Transplantation Surgery and Regenerative MedicineClinical Islet Transplant Program, University of Alberta, 2000 College Plaza, 8215-112th St, Edmonton T6G 2C8, Alberta, Canada
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15
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Andres A, Kin T, O'Gorman D, Livingstone S, Bigam D, Kneteman N, Senior P, Shapiro AMJ. Clinical islet isolation and transplantation outcomes with deceased cardiac death donors are similar to neurological determination of death donors. Transpl Int 2016; 29:34-40. [PMID: 26264982 DOI: 10.1111/tri.12650] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Revised: 06/12/2015] [Accepted: 08/02/2015] [Indexed: 02/05/2023]
Abstract
In islet transplantation, deceased cardiac death (DCD) donation has been identified as a potential extended source. There are currently no studies comparing outcomes between these categories, and our goal was to compare islet isolation success rates and transplantation outcomes between DCD and neurological determination of death (NDD) donors. Islet isolations from 15 DCD and 418 NDD were performed in our centre between September 2008 and September 2014. Donor variables, islet yields, metabolic function of isolated isled and insulin requirements at 1-month post-transplant were compared. Compared to NDD, pancreata from DCD were more often procured locally and donors required less vasopressive support (P < 0.001 and P = 0.023, respectively), but the other variables were similar between groups. Pre- and postpurification islet yields were similar between NDD and DCD (576 vs. 608 × 10(3) islet equivalent, P = 0.628 and 386 vs. 379, P = 0.881, respectively). The metabolic function was similar between NDD and DCD, as well as the mean decrease in insulin requirement at 1-month post-transplantation (NDD: 64.82%; DCD: 60.17% reduction, P = 0.517). These results support the broader use of DCD pancreata for islet isolation. A much larger DCD islet experience will be required to truly determine noninferiority of both short- and long-term outcomes.
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Affiliation(s)
- Axel Andres
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Doug O'Gorman
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Scott Livingstone
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - David Bigam
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Norman Kneteman
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Peter Senior
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
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16
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Khosravi-Maharlooei M, Hajizadeh-Saffar E, Tahamtani Y, Basiri M, Montazeri L, Khalooghi K, Kazemi Ashtiani M, Farrokhi A, Aghdami N, Sadr Hashemi Nejad A, Larijani MB, De Leu N, Heimberg H, Luo X, Baharvand H. THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away. Eur J Endocrinol 2015; 173:R165-R183. [PMID: 26036437 DOI: 10.1530/eje-15-0094] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 06/02/2015] [Indexed: 12/12/2022]
Abstract
Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges.
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Affiliation(s)
- Mohsen Khosravi-Maharlooei
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Yaser Tahamtani
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Mohsen Basiri
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Leila Montazeri
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Keynoosh Khalooghi
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Mohammad Kazemi Ashtiani
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Ali Farrokhi
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Nasser Aghdami
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Anavasadat Sadr Hashemi Nejad
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Mohammad-Bagher Larijani
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Nico De Leu
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Harry Heimberg
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Xunrong Luo
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran Department of Stem Cells and Developmental Biology at Cell Science Research CenterDepartment of Regenerative Medicine at Cell Science Research CenterRoyan Institute for Stem Cell Biology and Technology, ACECR, Tehran, IranEndocrinology and Metabolism Research InstituteTehran University of Medical Sciences, Tehran, IranDiabetes Research CenterVrije Universiteit Brussel, Laarbeeklaan 103, Brussels, BelgiumDivision of Nephrology and HypertensionDepartment of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USADepartment of Developmental BiologyUniversity of Science and Culture, ACECR, Tehran 148-16635, Iran
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17
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Berney T, Boffa C, Augustine T, Badet L, de Koning E, Pratschke J, Socci C, Friend P. Utilization of organs from donors after circulatory death for vascularized pancreas and islet of Langerhans transplantation: recommendations from an expert group. Transpl Int 2015; 29:798-806. [PMID: 26340064 DOI: 10.1111/tri.12681] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/15/2015] [Accepted: 08/26/2015] [Indexed: 12/26/2022]
Abstract
Donation after circulatory death (DCD) donors are increasingly being used as a source of pancreas allografts for vascularized organ and islet transplantation. We provide practice guidelines aiming to increase DCD pancreas utilization. We review risk assessment and donor selection criteria. We report suggested factors in donor and recipient clinical management and provide an overview of the activities and outcomes of vascularized pancreas and islet transplantation.
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Affiliation(s)
- Thierry Berney
- Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Catherine Boffa
- Nuffield Department of Surgery, Oxford Transplant Centre, University of Oxford, Oxford, UK
| | - Titus Augustine
- Department of Transplantation, Central Manchester University Hospitals, Manchester, UK
| | - Lionel Badet
- Division of Urology and Transplant Surgery, Hospices Civils de Lyon, Lyons, France
| | - Eelco de Koning
- Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
| | - Johann Pratschke
- Department of General, Visceral and Transplant Surgery, Charité-University Hospital, Berlin, Germany
| | - Carlo Socci
- Department of Surgery, Scientific Institute San Raffaele, Milan, Italy
| | - Peter Friend
- Nuffield Department of Surgery, Oxford Transplant Centre, University of Oxford, Oxford, UK
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18
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Kusamori K, Nishikawa M, Mizuno N, Nishikawa T, Masuzawa A, Tanaka Y, Mizukami Y, Shimizu K, Konishi S, Takahashi Y, Takakura Y. Increased Insulin Secretion from Insulin-Secreting Cells by Construction of Mixed Multicellular Spheroids. Pharm Res 2015; 33:247-56. [PMID: 26337771 DOI: 10.1007/s11095-015-1783-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/20/2015] [Indexed: 11/28/2022]
Abstract
PURPOSE We previously have shown that multicellular spheroids containing insulin-secreting cells are an effective therapy for diabetic mice. Here we attempted to increase insulin secretion by incorporating other cell types into spheroids. MATERIALS AND METHODS Multicellular spheroids of mouse MIN6 pancreatic β cells were formed in microwells alone and with aortic vascular endothelial MAEC cells or embryo fibroblast NIH3T3 cells. mRNA expression of insulin genes and insulin secretion of MIN6 cells in each spheroid were measured by real-time PCR and an insulin ELIZA kit. Moreover, collagen IV expression in each spheroid was analyzed by western blot. RESULTS In all cases, uniformly sized (about 300 μm) multicellular spheroids were obtained. MAEC or NIH3T3 cell incorporation into MIN6 spheroids significantly increased mRNA expression of insulin genes and insulin secretion. In addition, collagen IV expression, which was reported to enhance insulin secretion from pancreatic β cells, also increased in their spheroids. CONCLUSIONS The formation of mixed multicellular spheroids containing collagen IV-expressing cells can improve the insulin secretion from insulin-secreting MIN6 cells, and mixed multicellular spheroids can be a potent therapeutic option for patients with type I diabetes mellitus.
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Affiliation(s)
- Kosuke Kusamori
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Makiya Nishikawa
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan. .,Institute for Innovative NanoBio Drug Discovery and Development Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan. .,Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
| | - Narumi Mizuno
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Tomoko Nishikawa
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Akira Masuzawa
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yutaro Tanaka
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yuya Mizukami
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Kazunori Shimizu
- Institute for Innovative NanoBio Drug Discovery and Development Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.,Ritsumeikan-Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan
| | - Satoshi Konishi
- Institute for Innovative NanoBio Drug Discovery and Development Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.,Ritsumeikan-Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan.,Department of Mechanical Engineering, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan
| | - Yuki Takahashi
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.,Institute for Integrated Cell-Material Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Yoshinobu Takakura
- Department of Biopharmaceutics and Drug Metabolism Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.,Institute for Innovative NanoBio Drug Discovery and Development Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
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Hilling DE, Bouwman E, Terpstra OT, Marang-Van De Mheen PJ. Effects of Donor-, Pancreas-, and Isolation-Related Variables on Human Islet Isolation Outcome: A Systematic Review. Cell Transplant 2014; 23:921-8. [DOI: 10.3727/096368913x666412] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Different factors have been reported to influence islet isolation outcome, but their importance varies between studies and are hampered by the small sample sizes in most studies. The purpose of this study was to perform a systematic review to assess the impact of donor-, pancreas-, and isolation-related variables on successful human islet isolation outcome. PubMed, Embase, and Web of Science were searched electronically in April 2009. All studies reporting on donor-, pancreas-, and isolation-related factors relating to prepurification and postpurification islet isolation yield and proportion of successful islet isolations were selected. Seventy-four retrospective studies had sufficient data and were included in the analyses. Higher pre- and postpurification islet yields and a higher proportion of successful islet isolations were obtained when pancreata were preserved with the two-layer method rather than University of Wisconsin solution in donors with shorter cold ischemia times (CITs) [1 h longer CIT resulted in an average decline of prepurification and postpurification yields and proportion of successful isolations of 59 islet equivalents (IEQs)/g, 54 IEQs/g, and 21%, respectively]. Higher prepurification yields and higher percentage of successful islet isolations were found in younger donors with higher body mass index. Lower yields were found in donation after brain death donors compared to donation after cardiac death donors. Higher postpurification yields were found for isolation with Serva collagenase. This review identified donor-, pancreas-, and isolation-related factors that influence islet isolation yield. Standardized reports of these factors in all future studies may improve the power and identify additional factors and thereby contribute to improving islet isolation yield.
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Affiliation(s)
- Denise E. Hilling
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Eelco Bouwman
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Onno T. Terpstra
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
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20
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Anazawa T, Saito T, Goto M, Kenmochi T, Uemoto S, Itoh T, Yasunami Y, Kenjo A, Kimura T, Ise K, Tsuchiya T, Gotoh M. Long-Term Outcomes of Clinical Transplantation of Pancreatic Islets With Uncontrolled Donors After Cardiac Death: A Multicenter Experience in Japan. Transplant Proc 2014; 46:1980-4. [DOI: 10.1016/j.transproceed.2014.06.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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21
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Chhabra P, Brayman KL. Overcoming barriers in clinical islet transplantation: current limitations and future prospects. Curr Probl Surg 2014; 51:49-86. [PMID: 24411187 DOI: 10.1067/j.cpsurg.2013.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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The differential tissue expression of inflammatory, oxidative stress, and apoptosis markers in human uncontrolled non-heart-beating donors. Transplantation 2013; 95:1346-53. [PMID: 23542474 DOI: 10.1097/tp.0b013e31828ee151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Uncontrolled non-heart-beating donor (UNHBD) transplantation offers a major opportunity to ameliorate the effects of the donor shortage. However, little is known about the true status of the organs obtained from these donors. UNHBD transplantation is performed under unfavorable conditions and involves exposure to several harmful stimuli that have been identified as triggers for immediate inflammatory response, oxidative stress, and apoptotic phenomena. This adverse scenario could explain the higher rates of graft dysfunction due to primary nonfunction traditionally observed in NHBD. Our aim was to assess the expression of proinflammatory, oxidative, and apoptotic markers in liver, lung, and pancreas tissue samples obtained from UNHBD and to compare these expression levels with those observed in brain-dead donors (BDD). METHODS Samples from human type 2 NHBD and BDD were obtained at the end of cold storage. Interleukin (IL)-1β, tumor necrosis factor-α, IL-6, IL-10, endothelial nitric oxide synthase, inducible nitric oxide synthase, type 1 heme oxygenase, type 2 heme oxygenase, Bax, and Bcl-2 protein and mRNA expression, as well as catalase, glutathione peroxidase, and glutathione reductase tissue activity, were determined. RESULTS UNHBD showed similar or lower expression of proinflammatory mediators and apoptosis markers in all three organs without modifications to the anti-inflammatory cytokines. Although the major oxidative stress marker levels were also comparable in both types of donors, the type 1 heme oxygenase mRNA expression and antioxidant enzyme activity were slightly diminished in UNHBD. CONCLUSIONS The initial tissue damage generated during the UNHB donation process is at least comparable with that observed in BDD. However, although the expression of the immediate immune response and apoptosis markers is similar, a mild impairment of the local antioxidant activity was observed.
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Abstract
Clinical islet transplantation has progressed considerably over the past 12 years, and >750 patients with type 1 diabetes have received islet transplants internationally over this time. Many countries are beginning to accept the transition from research to accepted and funded clinical care, especially for patients with brittle control that cannot be stabilized by more conventional means. Major challenges remain, including the need for more than one donor, and the requirement for potent, chronic immunosuppression. Combining immunological tolerance both to allo- and autoantigens, and a limitless expandable source of stem cell- or xenograft-derived insulin-secreting cells represent remaining hurdles in moving this effective treatment to a potential cure for all those with type 1 or 2 diabetes.
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Affiliation(s)
- Michael McCall
- Clinical Islet Transplant Program and Department of Surgery, University of Alberta, Edmonton, Alberta T6G 2B7, Canada
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24
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Shapiro AMJ. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. Rev Diabet Stud 2012; 9:385-406. [PMID: 23804275 DOI: 10.1900/rds.2012.9.385] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Remarkable progress has been made in islet transplantation over a span of 40 years. Once just an experimental curiosity in mice, this therapy has moved forward, and can now provide robust therapy for highly selected patients with type 1 diabetes (T1D), refractory to stabilization by other means. This progress could not have occurred without extensive dynamic international collaboration. Currently, 1,085 patients have undergone islet transplantation at 40 international sites since the Edmonton Protocol was reported in 2000 (752 allografts, 333 autografts), according to the Collaborative Islet Transplant Registry. The long-term results of islet transplantation in selected centers now match registry data of pancreas-alone transplantation, with 6 sites reporting five-year insulin independence rates ≥50%. Islet transplantation has been criticized for the use of multiple donor pancreas organs, but progress has also occurred in single-donor success, with 10 sites reporting increased single-donor engraftment. The next wave of innovative clinical trial interventions will address instant blood-mediated inflammatory reaction (IBMIR), apoptosis, and inflammation, and will translate into further marked improvements in single-donor success. Effective control of auto- and alloimmunity is the key to long-term islet function, and high-resolution cellular and antibody-based assays will add considerable precision to this process. Advances in immunosuppression, with new antibody-based targeting of costimulatory blockade and other T-B cellular signaling, will have further profound impact on the safety record of immunotherapy. Clinical trials will move forward shortly to test out new human stem cell derived islets, and in parallel trials will move forward, testing pig islets for compatibility in patients. Induction of immunological tolerance to self-islet antigens and to allografts is a difficult challenge, but potentially within our grasp.
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Affiliation(s)
- A M James Shapiro
- Clinical Islet Transplant Program, University of Alberta, 2000 College Plaza, 8215 112th Street, Edmonton AB Canada T6G 2C8.
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Carbone M, Lerut J, Neuberger J. How regenerative medicine and tissue engineering may complement the available armamentarium in gastroenterology? World J Gastroenterol 2012; 18:6908-6917. [PMID: 23322988 PMCID: PMC3531674 DOI: 10.3748/wjg.v18.i47.6908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 09/10/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
The increasing shortage of donors and the adverse effects of immunosuppression have restricted the impact of solid organ transplantation. Despite the initial promising developments in xenotransplantation, roadblocks still need to be overcome and this form of organ support remains a long way from clinical practice. While hepatocyte transplantation may be effectively correct metabolic defects, it is far less effective in restoring liver function than liver transplantation. Tissue engineering, using extracellular matrix scaffolds with an intact but decellularized vascular network that is repopulated with autologous or allogeneic stem cells and/or adult cells, holds great promise for the treatment of failure of organs within gastrointestinal tract, such as end-stage liver disease, pancreatic insufficiency, bowel failure and type 1 diabetes. Particularly in the liver field, where there is a significant mortality of patients awaiting transplant, human bioengineering may offer a source of readily available organs for transplantation. The use of autologous cells will mitigate the need for long term immunosuppression thus removing a major hurdle in transplantation.
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Matsumoto S, Noguchi H, Naziruddin B, Onaca N, Jackson A, Nobuyo H, Teru O, Naoya K, Klintmalm G, Levy M. Improvement of pancreatic islet cell isolation for transplantation. Proc (Bayl Univ Med Cent) 2011; 20:357-62. [PMID: 17948109 DOI: 10.1080/08998280.2007.11928323] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Pancreatic islet transplantation is a promising treatment for diabetes but still faces several challenges. Poor islet isolation efficiency and poor long-term insulin independence are currently two major issues, although donor shortage and the need for immunosuppressants also need to be addressed. We established the Kyoto islet isolation method (KIIM), which has enabled us to isolate and transplant islets even from non-heart-beating donors. KIIM involves 1) cooling the donor pancreas in situ, 2) preserving the ducts with modified Kyoto solution, 3) using a modified two-layer pancreas preservation method, and 4) adjusting the density of the density gradient centrifugation and using an iodixanol-based solution for purification. KIIM has enabled us to transplant 17 islet preparations out of 21 isolations (an 81% success rate). All transplanted islets functioned, and all transplanted patients had improved glycemic control without hypoglycemic unawareness. Recently, we used KIIM for islet isolation from a brain-dead donor at Baylor, which resulted in a very high islet yield (789,984 IE) with high viability (100% by fluorescein diacetate/propidium iodide staining and a stimulation index of 4.7). This preliminary evidence suggests that KIIM may also be promising for islet isolation from brain-dead donors. In addition, to assess engrafted islet mass, we developed a secretory unit of islet transplant objects (SUITO) index: fasting C-peptide (ng/dL) / [fasting blood glucose (mg/dL) - 63] x 1500. This simple index has enabled us to monitor the engrafted islet mass. This index should be useful when deciding whether to perform additional islet transplantations to maintain insulin independence. Poor islet isolation efficacy and poor long-term results could be resolved with ongoing research.
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Affiliation(s)
- Shinichi Matsumoto
- Baylor Research Institute Islet Cell Laboratory, Fort Worth, Texas, USA.
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Sá GPD, Sogayar MC, Eliaschewitz FG, Genzini T, Letrinta R, Onari ES, Mantovani M, Labriola L, Matos D, Lopes-Filho GJ, Gonzalez AM, Mares-Guia TR. Islet versus pancreas transplantation in Brazil: Defining criteria for pancreas allocation decision. Islets 2011; 3:352-7. [PMID: 21983190 DOI: 10.4161/isl.3.6.17908] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Many studies have evaluated whether there are characteristics related to pancreas donors and the islet isolation process that can influence pancreatic islet yield. However, this analysis has not yet been performed in Brazil, one of the world leaders in whole pancreas organ transplantation (WOPT), where pancreas allocation for pancreatic islet transplantation (PIT) has no officially defined criteria. Definition of parameters that would predict the outcome of islet isolation from local pancreas donors would be useful for defining allocation priority in Brazil. OBJECTIVE To analyze the relationship between multiple donor-related and islet isolation variables with the total number of isolated pancreatic islet equivalents (IEQ) in a brazilian sample of pancreas donors. METHODS Several variables were analyzed in 74 pancreata relative to the outcome of total IEQs obtained at the end of the process. RESULTS In univariate analysis, body mass index (BMI) (p = 0.003), the presence of fatty infiltrates in the pancreas as observed during harvesting (p = 0.042) and pancreas digestion time (p = 0.046) were identified as variables related to a greater IEQ yield. In a multivariate analysis a statistically significant contribution to the variability of islet yield was found only for the BMI (p = 0.017). A ROC curve defined a BMI = 30 as a cut-off point, with pancreata from donors with BMI > 30 yielding more islets than donors with BMI < 30 (p< 0.001). CONCLUSION These data reinforce the importance of the donor BMI as a defining parameter for successful islet isolation and establishes this variable as a potential pancreas allocation criterion in Brazil, where there is unequal competition for good quality organs between WOPT and PIT.
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Affiliation(s)
- Gustavo P D Sá
- Gastrosurgery Division, Department of Surgery, Federal University of São Paulo-Escola Paulista de Medicina, São Paulo, SP, Brazil
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Pancreatic islets from non-heart-beating donor pig: two-layer preservation method in an in vitro porcine model. Int J Artif Organs 2011; 34:519-25. [PMID: 21725934 DOI: 10.5301/ijao.2011.8465] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2011] [Indexed: 11/20/2022]
Abstract
PURPOSE Pancreata from non-heart beating donors could represent an unlimited source of islets if their cell viability can be efficiently preserved during the time necessary to process the organs by the use of a better solution of preservation compared to the classic University of Wisconsin solution. The aim of this study was to determine whether it is possible to obtain functioning "alive islets" from non-heart-beating donors by comparing, on a porcine model, the classic "UW ice-store" method with a two-layer cold storage method (TLM) using oxygenated Perfluorocarbons (PFC) and UW. METHODS Whole pancreata were harvested from 20 NHBDs female pigs with similar characteristics and preserved for 4 h in UW solution (n = 10) or TLM (UW/PFC) solution (n=10). The isolated islets were then evaluated for number, viability, purity, and insulin secretion, also estimated after 8 weeks of cryopreservation. RESULTS The total number of islets obtained from isolation, and their function assayed by the insulin stimulation index, before and after cryopreservation, showed a higher value in the TLM group. No significative differences in terms of purity and viability before and after cryopreservation were found when comparing the two groups. CONCLUSIONS TLM solution for NHBDs porcine pancreata with cold ischemia time lower than 4 h offers significant advantages over UW solution storage, thereby increasing the isolation yield and isolation success rate of the pancreatic porcine islets.
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Pancreas procurement and preservation for islet transplantation: personal considerations. J Transplant 2011; 2011:783168. [PMID: 21918716 PMCID: PMC3171759 DOI: 10.1155/2011/783168] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 06/29/2011] [Accepted: 07/13/2011] [Indexed: 12/14/2022] Open
Abstract
Pancreatic islet transplantation is a promising option for the treatment of type 1 diabetic patients. After the successful demonstration of the Edmonton protocol, islet transplantation has advanced significantly on several fronts, including improved pancreas procurement and preservation systems. Since we frequently use pancreata from donors after cardiac death in Japan,we have applied the in situ regional organ cooling system for pancreas procurement to reduce the warm ischemic time. To reduce the apoptosis of pancreatic tissue during cold preservation, we have applied the ductal injection of preservation solution. For pancreas preservation, we use modified Kyoto solution, which is advantageous at trypsin inhibition and less collagenase inhibition. In this paper, we show pancreas procurement and preservation in our group for islet transplantation.
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Lu Y, Jin X, Chen Y, Li S, Yuan Y, Mai G, Tian B, Long D, Zhang J, Zeng L, Li Y, Cheng J. Mesenchymal stem cells protect islets from hypoxia/reoxygenation-induced injury. Cell Biochem Funct 2011; 28:637-43. [PMID: 21061411 DOI: 10.1002/cbf.1701] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hypoxia/reoxygenation (H/R)-induced injury is the key factor associated with islet graft dysfunction. This study aims to examine the effect of mesenchymal stem cells (MSCs) on islet survival and insulin secretion under H/R conditions. Islets from rats were isolated, purified, cultured with or without MSCs, and exposed to hypoxia (O(2) ≤ 1%) for 8 h and reoxygenation for 24 and 48 h, respectively. Islet function was evaluated by measuring basal and glucose-stimulated insulin secretion (GSIS). Apoptotic islet cells were quantified using Annexin V-FITC. Anti-apoptotic effects were confirmed by mRNA expression analysis of hypoxia-resistant molecules, HIF-1α, HO-1, and COX-2, using semi-quantitative retrieval polymerase chain reaction (RT-PCR). Insulin expression in the implanted islets was detected by immunohistological analysis. The main results show that the stimulation index (SI) of GSIS was maintained at higher levels in islets co-cultured with MSCs. The MSCs protected the islets from H/R-induced injury by decreasing the apoptotic cell ratio and increasing HIF-1α, HO-1, and COX-2 mRNA expression. Seven days after islet transplantation, insulin expression in the MSC-islets group significantly differed from that of the islets-alone group. We proposed that MSCs could promote anti-apoptotic gene expression by enhancing their resistance to H/R-induced apoptosis and dysfunction. This study provides an experimental basis for therapeutic strategies based on enhancing islet function.
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Affiliation(s)
- Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China.
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Islet transplantation using donors after cardiac death: report of the Japan Islet Transplantation Registry. Transplantation 2010; 90:740-7. [PMID: 20811319 DOI: 10.1097/tp.0b013e3181ecb044] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND This report summarizes outcomes of islet transplantation employing donors after cardiac death (DCD) between 2004 and 2007 as reported to the Japan Islet Transplantation Registry. METHOD Sixty-five islet isolations were performed for 34 transplantations in 18 patients with insulin-dependent diabetes mellitus, including two patients who had prior kidney transplantation. All but one donor (64/65) was DCD at the time of harvesting. RESULTS Factors influencing criteria for islet release included duration of low blood pressure of the donor, cold ischemic time, and usage of Kyoto solution for preservation. Multivariate analysis selected usage of Kyoto solution as most important. Of the 18 recipients, 8, 4, and 6 recipients received 1, 2, and 3 islet infusions, respectively. Overall graft survival defined as C-peptide level more than or equal to 0.3 ng/mL was 76.5%, 47.1%, and 33.6% at 1, 2, and 3 years, respectively, whereas corresponding graft survival after multiple transplantations was 100%, 80.0%, and 57.1%, respectively. All recipients remained free of severe hypoglycemia while three achieved insulin independence for 14, 79, and 215 days. HbA1c levels and requirement of exogenous insulin were significantly improved in all patients. CONCLUSION Islet transplantation employing DCD can ameliorate severe hypoglycemic episodes, significantly improve HbA1c levels, sustain significant levels of C-peptide, and achieve insulin independence after multiple transplantations. Thus, DCD can be an important resource for islet transplantation if used under strict releasing criteria and in multiple transplantations, particularly in countries where heart-beating donors are not readily available.
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Kaddis JS, Danobeitia JS, Niland JC, Stiller T, Fernandez LA. Multicenter analysis of novel and established variables associated with successful human islet isolation outcomes. Am J Transplant 2010; 10:646-56. [PMID: 20055802 PMCID: PMC2860018 DOI: 10.1111/j.1600-6143.2009.02962.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Islet transplantation is a promising therapy used to achieve glycometabolic control in a select subgroup of individuals with type I diabetes. However, features that characterize human islet isolation success prior to transplantation are not standardized and lack validation. We conducted a retrospective analysis of 806 isolation records from 14 pancreas-processing laboratories, considering variables from relevant studies in the last 15 years. The outcome was defined as post-purification islet equivalent count, dichotomized into yields > or =315 000 or < or =220 000. Univariate analysis showed that donor cause of death and use of hormonal medications negatively influenced outcome. Conversely, pancreata from heavier donors and those containing elevated levels of surface fat positively influence outcome, as did heavier pancreata and donors with normal amylase levels. Multivariable logistic regression analysis identified the positive impact on outcome of surgically intact pancreata and donors with normal liver function, and confirmed that younger donors, increased body mass index, shorter cold ischemia times, no administration of fluid/electrolyte medications, absence of organ edema, use of University of Wisconsin preservation solution and a fatty pancreas improves outcome. In conclusion, this multicenter analysis highlights the importance of carefully reviewing all donor, pancreas and processing parameters prior to isolation and transplantation.
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Affiliation(s)
- J S Kaddis
- Administrative and Bioinformatics Coordinating Center, Division of Information Sciences, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
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Pepper AR, Gall C, Mazzuca DM, Melling CWJ, White DJG. Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts. Xenotransplantation 2010; 16:502-10. [PMID: 20042050 DOI: 10.1111/j.1399-3089.2009.00548.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Islet transplantation is potentially a promising therapy for the restoration of carbohydrate control to diabetic patients. However, the global application of islet transplantation requires a ubiquitous source of beta cells. The xenotransplantation of porcine islets would provide such a source. Success in porcine islet xenografting has been achieved in diabetic primates. However, there are few reports of reversal of diabetes with porcine islet xenografts in rodent models of diabetes, relative to the number of successful rodent experiments performed as allografts. Here we report for the first time the inability of porcine (and human) insulin to control blood glucose levels in diabetic rodents determined by a series of dose escalating studies. METHODS Insulin was administered intravenously to streptozotocin induced diabetic Lewis rats, Balb/c and athymic Balb/c mice (n = 5 per group) at the following doses: Group I "physiological dose" (pd) of 0.16 U/kg for a total dose of 40 mU to a 250 g rat. Group II received 0.64 U/kg (4xpd), group III 1.6 U/kg (10xpd) and group IV 6.4 U/kg (40xpd). Blood glucose levels were monitored in each animal at seven time points: 0 (pre-injection), 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h and 3 h post-injection. Serum insulin levels were also determined. RESULTS Diabetic Lewis rats achieved a maximum reduction in blood glucose from 22.1 +/- 1.8mmol/l to 8.0 +/- 3.1 mmol/l (a 63.7% reduction), 90 minutes post-injection of 6.4 U/kg dose of porcine insulin (40xpd). Human insulin was less effective at reducing blood glucose levels in rats than porcine insulin (P < 0.001). Porcine insulin reduced blood glucose levels in Balb/c mice from a mean of 18.2 +/- 2.1 mmol/l to a hypoglycemic minimum of 1.26 +/- 0.18 mmol/l a reduction of 93.0%, 60 min post-injection of the maximum dose of 6.4 U/kg. Balb/c mice were significantly more responsive to porcine insulin than Lewis rats at doses of 0.64 U/kg (P < 0.001), 1.6 U/kg (P < 0.05) and 6.4 U/kg (P < 0.001). Athymic Balb/c nude mice reached a maximum reduction in blood glucose from 21.6 +/- 1.8 mmol/l to 3.6 +/- 0.9 mmol/l (a 83.4% reduction) 120 min post-injection at a dose of 6.4 U/kg. Overall, athymic Balb/c nude mice were more resistant to porcine insulin than immunocompetent Balb/c mice at doses of 0.64 U/kg (P < 0.001), 1.6 U/kg (P < 0.001) and 6.4 U/kg (P < 0.05). Insulin diluent alone marginally increased blood glucose levels in all animals tested. CONCLUSIONS Our results suggest that restoration of normoglycemia in diabetic rodents is not ideal for testing porcine islets xenografts since the reversals of diabetes in these species requires 20 to 40 times the dose of porcine insulin used in humans.
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Affiliation(s)
- Andrew R Pepper
- Department of Pathology, University of Western Ontario, London, Canada
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Microassay for glucose-induced preproinsulin mRNA expression to assess islet functional potency for islet transplantation. Transplantation 2010; 89:146-54. [PMID: 20098276 DOI: 10.1097/tp.0b013e3181c4218d] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The capacity for insulin synthesis in islets is important for islet transplantation to succeed. We developed a microassay that evaluates the potency of human islets by measuring changes in glucose-induced human insulin gene (INS) expression using a single islet in octuplicate samples. METHODS Poly (A) messenger RNA (mRNA) was purified from a set of single handpicked human islets. Glucose-induced mature (postspliced) and premature (prespliced) insulin mRNA were quantified by reverse-transcriptase polymerase chain reaction using several insulin mRNA primers designed at different locations including, intron, exon, and an exon-intron junction. RESULTS The synthesis of premature INS mRNA was significantly increased in islets exposed to high glucose for 16 vs. 4 hr (P<0.01), whereas mature INS mRNA showed no difference. Glucose-induced premature INS mRNA synthesis was attenuated in heat-damaged islets. Stimulation index (SI) calculated by normalizing premature by mature INS mRNA (SI_INS mRNA) positively correlated with SI of insulin release (SI_16h insulin) from the same set of islets during 16-hr incubation in high or low glucose media, and SI of glucose-mediated insulin release obtained from the same islet lot in a perifusion system (n=12). Furthermore, linear multiple regression analysis using SI_INS mRNA and SI_16h insulin predicted islet transplantation outcome in nonobese diabetic (NOD) scid mice (n=8). CONCLUSION The measurement of glucose-induced premature INS mRNA normalized by mature INS mRNA can be used to assess the functional quality of human islets and may predict islet function after transplantation in type 1 diabetic patients.
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Moers C, Leuvenink HGD, Ploeg RJ. Donation after cardiac death: evaluation of revisiting an important donor source. Nephrol Dial Transplant 2010; 25:666-73. [PMID: 20061321 DOI: 10.1093/ndt/gfp717] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Ridgway D, Manas D, Shaw J, White S. Preservation of the donor pancreas for whole pancreas and islet transplantation. Clin Transplant 2010; 24:1-19. [DOI: 10.1111/j.1399-0012.2009.01151.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Noguchi H, Levy MF, Kobayashi N, Matsumoto S. Pancreas preservation by the two-layer method: does it have a beneficial effect compared with simple preservation in University of Wisconsin solution? Cell Transplant 2009; 18:497-503. [PMID: 19775509 DOI: 10.1177/096368970901805-603] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
A large number of reports have shown that the two-layer method (TLM), which employs oxygenated perfluorochemical (PFC) and University of Wisconsin (UW) solution, is superior to simple cold storage in UW in islet transplantation. However, two recent large-scale studies showed no beneficial effect of TLM compared with UW storage in human islet transplantation. We reevaluated the effect of TLM by following three groups: group 1: UW simple storage; group 2: TLM performed by multiorgan procurement teams (not specialists of islet isolation); and group 3: TLM performed by specialists of islet isolation (Noguchi and Matsumoto). There were no significant differences between groups 1 and 2, whereas islet yields were significantly higher in group 3 compared with either group 1 or 2. Our data suggest that exact, complete performance of TLM could improve the outcome of islet isolation and transplantation. In this review, we describe the mechanisms of the TLM, the procedure of preoxygenated TLM, and the several possibilities for the reasons of the discrepancy.
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Affiliation(s)
- Hirofumi Noguchi
- Baylor Institute for Immunology Research/Baylor All Saints Medical Center, Baylor Research Institute, Dallas, TX, USA.
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Noguchi H, Ueda M, Hayashi S, Kobayashi N, Okitsu T, Iwanaga Y, Nagata H, Liu X, Kamiya H, Levy MF, Matsumoto S. Comparison of trypsin inhibitors in preservation solution for islet isolation. Cell Transplant 2009; 18:541-7. [PMID: 19775515 DOI: 10.1177/096368970901805-609] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Islet transplantation has recently emerged as an effective therapy and potential cure for type 1 diabetes mellitus. Recent reports show that the two-layer method (TLM), which employs oxygenated perfluorochemical (PFC) and University of Wisconsin (UW) solution, is superior to simple cold storage in UW for pancreas preservation in islet transplantation. Moreover, we recently reported that islet yield was significantly higher in the ET-Kyoto solution with ulinastatin (MK)/PFC preservation solution compared with the UW/PFC preservation solution in the porcine model and that the advantages of MK solution are trypsin inhibition and less collagenase inhibition. In this study, we compared ulinastatin with another trypsin inhibitor, Pefabloc, in preservation solution for islet isolation. Islet yield before purification was higher in the MK/PFC group compared with the ET-Kyoto with Pefabloc (PK)/PFC group. The stimulation index was higher for the MK/PFC group than for the PK/PFC group. These data suggest that ET-Kyoto with ulinastatin was the better combination for pancreas preservation than ET-Kyoto with Pefabloc. Based on these data, we now use ET-Kyoto solution with ulinastatin for clinical islet transplantation.
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Affiliation(s)
- Hirofumi Noguchi
- Transplantation Unit, Kyoto University Hospital, Kyoto 606-8507, Japan.
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Casanova D. [Pancreatic islets transplantation in the treatment of diabetes mellitus: present and future]. Cir Esp 2009; 85:76-83. [PMID: 19231462 DOI: 10.1016/j.ciresp.2008.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Accepted: 07/23/2008] [Indexed: 12/01/2022]
Abstract
Diabetes treatment with insulin does no prevent the development of secondary complications. For this reason, treatments other than conventional ones are needed, which could bring about an < > metabolic regulation. This can only be done by transplanting insulin producing tissue, such as vascularised pancreas transplantation, which is an already consolidated clinical procedure these days, or by islets transplantation, which is still a procedure in the clinical research phase. This has the same metabolic objectives as the vascularised transplant, but without the risks of major abdominal surgery, since the islets are implanted in the liver with minimal surgery or using interventionist radiology by means of a catheter. A clinical trial (Edmonton Protocol) was published in the year 2000, which improved the results after islet transplantation by obtaining normoglycaemia periods of more than one year in a consecutive patient series with type 1 diabetes and without using corticoids. This protocol has been endorsed in other centre in different trials. Although the initial results were good, the progress of these patients has shown that many islets transplantations do not manage to maintain insulin-independence indefinitely.
Affiliation(s)
- Daniel Casanova
- Servicio de Cirugía General y Digestiva, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Cantabria, España.
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Abstract
PURPOSE OF REVIEW The present review investigates donor qualities that impact pancreas and islet transplantation, with a focus on donors that have been historically underutilized, including those of extreme age, extreme size, and donors after cardiac death. RECENT FINDINGS The increasing waiting time caused by the shortage of available pancreata and the growing number of patients with uncontrolled diabetes has led to the expansion of acceptance criteria for transplantable pancreata. The possible increased perioperative risks and/or foreshortened graft survival associated with the use of 'extreme' donors should be weighed against the mortality of uremic diabetics on the waiting list and the risk of dying from a hypoglycemic-unawareness episode. Current data have shown that pediatric pancreas donors are associated with excellent outcomes. Selected donors up to 50 years of age are suitable for both islet and pancreas transplantation. Obese donors are more appropriate as islet donors, and donors after cardiac death provide an underutilized source of pancreata for transplantation, with clinical results that are identical to those observed from ideal donors. SUMMARY Donor selection in pancreas transplantation significantly impacts outcome, yet the use of extended criteria donors can provide results comparable with those of ideal donors.
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Kung HF, Lieberman BP, Zhuang ZP, Oya S, Kung MP, Choi SR, Poessl K, Blankemeyer E, Hou C, Skovronsky D, Kilbourn M. In vivo imaging of vesicular monoamine transporter 2 in pancreas using an (18)F epoxide derivative of tetrabenazine. Nucl Med Biol 2008; 35:825-37. [PMID: 19026944 PMCID: PMC2632775 DOI: 10.1016/j.nucmedbio.2008.08.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 08/20/2008] [Accepted: 08/31/2008] [Indexed: 10/21/2022]
Abstract
OBJECTIVES Development of imaging agents for pancreatic beta cell mass may provide tools for studying insulin-secreting beta cells and their relationship with diabetes mellitus. In this paper, a new imaging agent, [(18)F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline [(18)F](+)4, which displays properties targeting vesicular monoamine transporter 2 (VMAT2) binding sites of beta cells in the pancreas, was evaluated as a positron emission tomography (PET) agent for estimating beta cell mass in vivo. The hydrolyzable epoxide group of (+)4 may provide a mechanism for shifting biodistribution from liver to kidney, thus reducing the background signal. METHODS Both (18)F- and (19)F-labeled (+) and (-) isomers of 4 were synthesized and evaluated. Organ distribution was carried out in normal rats. Uptake of [(18)F](+)4 in pancreas of normal rats was measured and correlated with blocking studies using competing drugs, (+)dihydrotetrabenazine [(+)-DTBZ] or 9-fluoropropyl-(+)dihydro tetrabenazine [FP-(+)-DTBZ, (+)2]. RESULTS In vitro binding study of VMAT2 using rat brain striatum showed a K(i) value of 0.08 and 0.15 nM for the (+)4 and (+/-)4, respectively. The in vivo biodistribution of [(18)F](+)4 in rats showed the highest uptake in the pancreas (2.68 %ID/g at 60 min postinjection). In vivo competition experiments with cold FP-(+)-DTBZ, (+)2, (3.5 mg/kg, 5 min iv pretreatment) led to a significant reduction of pancreas uptake (85% blockade at 60 min). The inactive isomer [(18)F](-)4 showed significantly lower pancreas uptake (0.22 %ID/g at 30 min postinjection). Animal PET imaging studies of [(18)F](+)4 in normal rats demonstrated an avid pancreatic uptake in rats. CONCLUSION The preliminary results suggest that the epoxide, [(18)F](+)4, is highly selective in binding to VMAT2 and it has an excellent uptake in the pancreas of rats. The liver uptake was significantly reduced through the use of the epoxide group. Therefore, it may be potentially useful for imaging beta cell mass in the pancreas.
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Affiliation(s)
- Hank F Kung
- Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Abstract
PURPOSE OF REVIEW To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. RECENT FINDINGS Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture desirable before islet isolation and transplantation and may improve islet yield and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet-potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas-preservation and islet-isolation strategies. SUMMARY Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold-storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes.
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Liu X, Matsumoto S, Okitsu T, Iwanaga Y, Noguchi H, Yonekawa Y, Nagata H, Kamiya H, Ueda M, Hatanaka N, Miyakawa S, Kobayashi N, Song C. Analysis of donor- and isolation-related variables from non-heart-beating donors (NHBDs) using the Kyoto islet isolation method. Cell Transplant 2008; 17:649-56. [PMID: 18819253 DOI: 10.3727/096368908786092711] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Recently, we demonstrated that islet transplantation from non-heart-beating donors (NHBDs) using the Kyoto islet isolation method (KIIM) successfully reversed patients' diabetes state. In this study, we evaluated the effects of donor- and isolation-related variables on islet isolation results from NHBDs by KIIM. Twenty-one islet preparations from the pancreata of NHBDs were isolated by KIIM. Islet preparations that met transplantation criteria and achieved improved patient diabetes control after transplantation were defined as successful isolations. Potential risk factors deemed to affect islet isolation results, such as age, gender, body mass index, hospital stay, donors' blood biochemical tests, a modified pancreata procurement method, and isolation and purification procedure-related variables, were analyzed. Seventeen out of 21 islet isolations (81%) were successful isolations. Postpurification islet yield was 447,639 +/- 39,902 islet equivalents (IE) in the successful isolation group and 108,007 +/- 31,532 IE in the failure group. Donor age was significantly younger in the success group (41.9 +/- 4.0 years old in the success group vs. 57.5 +/- 2.2 years old in the failure group, p = 0.003). Chronic pancreatitis significantly decreased islet yields (p = 0.006). Phase I time was significantly shorter (p = 0.010) and undigested tissue volume was significantly smaller (p = 0.020) in the success group. Purity was in positive correlation to postpurification islet yield, while donor age was in reverse correlation to postpurification islet yield. KIIM enables us to perform islet transplantation from NHBDs; however, the decision to use pancreata from older donors or those with chronic pancreatitis requires careful consideration.
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Affiliation(s)
- Xiaoling Liu
- General Surgery, First Clinical College of Harbin Medical University, Harbin, PR China
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Wilson JT, Chaikof EL. Thrombosis and inflammation in intraportal islet transplantation: a review of pathophysiology and emerging therapeutics. J Diabetes Sci Technol 2008; 2:746-59. [PMID: 19885257 PMCID: PMC2769789 DOI: 10.1177/193229680800200502] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
With the inception of the Edmonton Protocol, intraportal islet transplantation (IPIT) has re-emerged as a promising cell-based therapy for type 1 diabetes. However, current clinical islet transplantation remains limited, in part, by the need to transplant islets from 2-4 donor organs, often through several separate infusions, to reverse diabetes in a single patient. Results from clinical islet transplantation and experimental animal models now indicate that the majority of transplanted islets are destroyed in the immediate post-transplant period, a process largely facilitated by deleterious inflammatory responses triggered by islet-derived procoagulant and proinflammatory mediators. Herein, mechanisms that underlie the pathophysiology of thrombosis and inflammation in IPIT are reviewed, and emerging approaches to improve islet engraftment through attenuation of inflammatory responses are discussed.
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Affiliation(s)
- John T. Wilson
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
| | - Elliot L. Chaikof
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
- School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia
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Iwanaga Y, Sutherland DE, Harmon JV, Papas KK. Pancreas preservation for pancreas and islet transplantation. Curr Opin Organ Transplant 2008; 13:445-51. [PMID: 18685343 PMCID: PMC2858000 DOI: 10.1097/mot.0b013e328303df04] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. RECENT FINDINGS Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas and islet transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture. Pancreas perfusion may be desirable before islet isolation and transplantation and may improve islet yields and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas preservation and islet isolation strategies. SUMMARY Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes.
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Affiliation(s)
- Yasuhiro Iwanaga
- Transplantation Unit, Kyoto University Hospital, Kyoto, Japan
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
| | - David E.R. Sutherland
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
| | - James V. Harmon
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
| | - Klearchos K. Papas
- Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, USA
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Kung MP, Hou C, Lieberman BP, Oya S, Ponde DE, Blankemeyer E, Skovronsky D, Kilbourn MR, Kung HF. In vivo imaging of beta-cell mass in rats using 18F-FP-(+)-DTBZ: a potential PET ligand for studying diabetes mellitus. J Nucl Med 2008; 49:1171-6. [PMID: 18552132 DOI: 10.2967/jnumed.108.051680] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
UNLABELLED Recent studies on gene expression of beta-cell mass (BCM) in the pancreas showed that vesicular monoamine transporter 2 (VMAT2) is highly expressed in the BCM (mainly in the islets of Langerhans). Imaging pancreatic BCM may provide an important tool for understanding the relationship between loss of insulin-secreting beta-cells and onset of diabetes mellitus. In this article, 9-fluoropropyl-(+)-dihydrotetrabenazine (FP-(+)-DTBZ), which is a VMAT2 imaging agent, was evaluated as a PET agent for estimating BCM in vivo. METHODS Organ biodistribution after an intravenous injection of (18)F-FP-(+)-DTBZ (active isomer) and (18)F-FP-(-)-DTBZ (inactive isomer) was evaluated in normal rats. The specificity of uptake of (18)F-FP-(+)-DTBZ was assessed by a pretreatment (3.8 mg of (+)-DTBZ per kilogram and 3.5 mg of FP-(+)-DTBZ per kilogram, intravenously, 5 min prior) or coadministration (2 mg of (+)-DTBZ per kilogram). PET studies were performed in normal rats. RESULTS The in vivo biodistribution of (18)F-FP-(+)-DTBZ in rats showed the highest uptake in the pancreas (5% dose/g at 30 min after injection), whereas (18)F-FP-(-)-DTBZ showed a very low pancreas uptake. Rats pretreated with FP-(+)-DTBZ displayed a 78% blockade of pancreas uptake. PET studies in normal rats demonstrated an avid pancreas uptake of (18)F-FP-(+)-DTBZ. CONCLUSION The preliminary data obtained with (18)F-FP-(+)-DTBZ suggest that this fluorinated derivative of DTBZ shows good pancreas specificity and has the potential to be useful for quantitative measurement of VMAT2 binding sites reflecting BCM in the pancreas.
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Affiliation(s)
- Mei-Ping Kung
- Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Noguchi H, Matsumoto S. Islet transplantation at the Diabetes Research Institute Japan. JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY 2008; 15:278-83. [PMID: 18535765 DOI: 10.1007/s00534-007-1263-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2006] [Accepted: 08/15/2007] [Indexed: 01/29/2023]
Abstract
Since the Edmonton Protocol was announced, more than 600 patients with type 1 diabetes at more than 50 institutions have received islet transplantation to treat their disease. We recently established a new islet isolation protocol, called the Kyoto Islet Isolation Method, based on the Ricordi method. It includes an in-situ cooling system for pancreas procurement, pancreatic ductal protection, a modified two-layer (M-Kyoto /perfluorochemical [PFC]) method of pancreas preservation, and a new islet purification solution (Iodixanol-based solution). Using this islet isolation method, we isolated islets from 19 human pancreata of non-heart-beating donors and transplanted 16 preparations into seven patients with type 1 diabetes between April 7, 2004 and November 18, 2005. The percentage of those meeting the release criteria of the Edmonton Protocol was more than 80%. We also performed living-donor transplantation of islets for unstable diabetes on January 19, 2005. Establishment of this method enables us to make diabetic patients insulin-independent, using islets not only from two or three pancreata of non-heart-beating donors but also using islets from half a pancreas from a living donor.
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Noguchi H, Yamada Y, Okitsu T, Iwanaga Y, Nagata H, Kobayashi N, Hayashi S, Matsumoto S. Secretory unit of islet in transplantation (SUIT) and engrafted islet rate (EIR) indexes are useful for evaluating single islet transplantation. Cell Transplant 2008; 17:121-8. [PMID: 18468242 DOI: 10.3727/000000008783906991] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The evaluation of engraftment is important to assess the success of islet transplantation, but it is complex because islet transplantation usually requires two or more donors to achieve euglycemia. Islet transplantation from NHBDs was evaluated using new assessment forms for the secretory unit of islet in transplantation (SUIT) and engrafted islet rate (EIR) indexes. Insulin independence was obtained when the SUIT index was more than 28, which might indicate that 28% of the beta-cell mass of a normal subject is required for insulin independence. Because the average EIR for a single transplantation is about 30, the percentage of engrafted islets following one transplantation is about 30%, assuming that a normal subject has 1 million islet equivalents. Although few cultured islet transplants have been performed, the increase of the SUIT and EIR indexes in patients who received cultured islets was significantly lower than in patients who received fresh islets, suggesting that fresh islets may be more effective than cultured islets. The SUIT and EIR indexes are thus considered to be useful values for evaluating islet transplantation, especially for single islet transplantation.
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Affiliation(s)
- Hirofumi Noguchi
- Transplantation Unit, Kyoto University Hospital, Kyoto 606-8507, Japan.
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Ponte GM, Pileggi A, Messinger S, Alejandro A, Ichii H, Baidal DA, Khan A, Ricordi C, Goss JA, Alejandro R. Toward maximizing the success rates of human islet isolation: influence of donor and isolation factors. Cell Transplant 2007; 16:595-607. [PMID: 17912951 DOI: 10.3727/000000007783465082] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
In order to make islet transplantation a therapeutic option for patients with diabetes there is an urgent need for more efficient islet cell processing to maximize islet recovery. Improved donor management, organ recovery techniques, implementation of more stringent donor criteria, and improved islet cell processing techniques may contribute to enhance organ utilization for transplantation. We have analyzed the effects of donor and islet processing factors on the success rate of human islet cell processing for transplantation performed at a single islet cell processing center. Islet isolation outcomes improved when vasopressors, and in particular pitressin, and steroids were used for the management of multiorgan donors. Higher islet yields were obtained from adult male donors, BMI >25 kg/m2, adequate glycemic control during hospital stay, and when the pancreas was retrieved by a local surgical team. Successful isolations were obtained in 58% of the cases when > or = 4 donor criteria were met, and even higher success rates (69%) were observed when considering > or = 5 criteria. Our data suggest that a sequential, integrated approach is highly desirable to improve the success rate of islet cell processing.
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Affiliation(s)
- Gaston M Ponte
- Cell Transplant Center and Clinical Islet Transplant Center, Diabetes Research Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
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Zhao M, Muiesan P, Amiel SA, Srinivasan P, Asare-Anane H, Fairbanks L, Persaud S, Jones P, Jones J, Ashraf S, Littlejohn W, Rela M, Heaton N, Huang GC. Human islets derived from donors after cardiac death are fully biofunctional. Am J Transplant 2007; 7:2318-25. [PMID: 17845565 DOI: 10.1111/j.1600-6143.2007.01937.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Islets from brain-dead donors (BDDs) are being used in the treatment of Type 1 diabetes. However, both donor numbers and islet survival are limited. We explored the clinical potential for islets from non-heart-beating donors (NHBDs), who have lower circulating cytokines, by comparing islets from 10 NHBDs against 12 identically-isolated islets from BDDs over the same time period. The quantity and quality of islets from NHBDs was good. NHBD yielded approximately 12.6% more islets than those of BDDs (505,000 +/- 84,230 vs. 400,970 +/- 172,430 islet equivalent number [IEQ]/pancreas, p = 0.01) with comparable viability. ATP and GTP contents were lower (6.026 +/- 3.076 vs. 18.105 +/- 7.8 nM/mg protein, p = 0.01 and 1.52 +/- 0.87 vs. 3.378 +/- 0.83 nM/mg protein, p = 0.04) and correlated negatively to warm ischemia time (R(2)= 0.8022 and R(2)= 0.7996, respectively). Islets from NHBDs took longer to control hyperglycemia in diabetic mice, but were equally able to sustain euglycemia. With a warm ischemia time (WIT) of <or=25 min, islets from NHBDs are at least as competent as islets from BDDs and should be suitable for clinical use.
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Affiliation(s)
- M Zhao
- Diabetes Research Group, King's College London School of Medicine, London, UK
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