Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival
Background: Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including donor shortage, prevention of islet necrosis and loss in pre- and post-transplantation, and optimization of immunosuppression. This study seeks to determine the cause of necrotic loss of isolated islets to improve transplant efficiency. Methodology: The oxygen tension inside isolated human islets of different sizes was simulated under varying oxygen environments using a computational in silico model. In vitro human islet viability was also assessed after culturing in different oxygen conditions. Correlation between simulation data and experimentally measured islet viability was examined. Using these in vitro viability data of human islets, the effect of islet diameter and oxygen tension of the culture environment on islet viability was also analyzed using a logistic regression model. Principal findings: Computational simulation clearly revealed the oxygen gradient inside the islet structure. We found that oxygen tension in the islet core was greatly lower (hypoxic) than that on the islet surface due to the oxygen consumption by the cells. The hypoxic core was expanded in the larger islets or in lower oxygen cultures. These findings were consistent with results from in vitro islet viability assays that measured central necrosis in the islet core, indicating that hypoxia is one of the major causes of central necrosis. The logistic regression analysis revealed a negative effect of large islet and low oxygen culture on islet survival. Conclusions/Significance: Hypoxic core conditions, induced by the oxygen gradient inside islets, contribute to the development of central necrosis of human isolated islets. Supplying sufficient oxygen during culture could be an effective and reasonable method to maintain isolated islets viable.
Additional Information© 2017 Komatsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: March 16, 2017; Accepted: August 10, 2017; Published: August 23, 2017. All relevant data are within the paper and its Supporting Information files. This work was supported by a grant from the Nora Eccles Treadwell Foundation (30.6990.973667). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank United Network for Organ Sharing (UNOS) for providing donated organs used for isolating human islets. Isolated islets were provided by Southern California Islet Cell Resources (SC-ICR) Center of City of Hope following standard operation procedures approved by our Institutional Review Board and the FDA. We acknowledge the Manufacture Team led by Dr. Ismail Al-Abdullah at the SC-ICR, Beckman Research Institute of City of Hope for preparation of human islets. We also thank Dr. Hung-Ping Shih for providing alpha TC1 clone 6 cells, and Dr. Chris Gandhi for critical reading and editing of the manuscript. Author Contributions: Conceptualization: Hirotake Komatsu. Data curation: Hirotake Komatsu, Colin Cook, Chia-Hao Wang, Leonard Medrano. Formal analysis: Hirotake Komatsu, Colin Cook, Chia-Hao Wang. Funding acquisition: Yoko Mullen. Investigation: Hirotake Komatsu, Colin Cook, Leonard Medrano. Methodology: Hirotake Komatsu, Colin Cook, Chia-Hao Wang. Project administration: Henry Lin. Resources: Henry Lin. Supervision: Fouad Kandeel, Yu-Chong Tai, Yoko Mullen. Visualization: Hirotake Komatsu, Colin Cook, Chia-Hao Wang. Writing ± original draft: Hirotake Komatsu. Writing ± review & editing: Hirotake Komatsu, Yoko Mullen.
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