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Yue L, Li J, Yao M, Song S, Zhang X, Wang Y. Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation. Front Immunol 2024; 15:1455691. [PMID: 39346923 PMCID: PMC11427288 DOI: 10.3389/fimmu.2024.1455691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.
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Affiliation(s)
- Liting Yue
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingjun Yao
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Xiaoqin Zhang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Chengdu, China
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2
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Fagundes RR, Zaldumbide A, Taylor CT. Role of hypoxia-inducible factor 1 in type 1 diabetes. Trends Pharmacol Sci 2024; 45:798-810. [PMID: 39127527 DOI: 10.1016/j.tips.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 08/12/2024]
Abstract
Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in β-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics.
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Affiliation(s)
- Raphael R Fagundes
- Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands
| | - Cormac T Taylor
- School of Medicine and Conway Institute of Biomolecular and Biomedical Research and Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
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3
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Inagaki NF, Oki Y, Ikeda S, Tulakarnwong S, Shinohara M, Inagaki FF, Ohta S, Kokudo N, Sakai Y, Ito T. Transplantation of pancreatic beta-cell spheroids in mice via non-swellable hydrogel microwells composed of poly(HEMA- co-GelMA). Biomater Sci 2024; 12:4354-4362. [PMID: 38967234 DOI: 10.1039/d4bm00295d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
Pancreatic islet transplantation is an effective treatment for type I diabetes mellitus. However, many problems associated with pancreatic islet engraftment remain unresolved. In this study, we developed a hydrogel microwell device for islet implantation, fabricated by crosslinking gelatin-methacryloyl (GelMA) and 2-hydroxyethyl methacrylate (HEMA) in appropriate proportions. The fabricated hydrogel microwell device could be freeze-dried and restored by immersion in the culture medium at any time, allowing long-term storage and transport of the device for ready-to-use applications. In addition, due to its non-swelling properties, the shape of the wells of the device was maintained. Thus, the device allowed pancreatic β cell lines to form spheroids and increase insulin secretion. Intraperitoneal implantation of the β cell line-seeded GelMA/HEMA hydrogel microwell device reduced blood glucose levels in diabetic mice. In addition, they were easy to handle during transplantation and were removed from the transplant site without peritoneal adhesions or infiltration by inflammatory cells. These results suggest that the GelMA/HEMA hydrogel microwell device can go from spheroid and/or organoid fabrication to transplantation in a single step.
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Affiliation(s)
- Natsuko F Inagaki
- Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Chemical System Engineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
| | - Yuichiro Oki
- Department of Chemical System Engineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
| | - Shunsuke Ikeda
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Sarun Tulakarnwong
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Marie Shinohara
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
- Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
| | - Fuyuki F Inagaki
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Seiichi Ohta
- Department of Chemical System Engineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
- Institute of Engineering Innovation, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Taichi Ito
- Department of Chemical System Engineering, School of Engineering, The University of Tokyo, Tokyo, Japan.
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
- Center for Disease Biology and Integrative Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Leishman DJ, Oppler SH, Stone LLH, O’Brien TD, Ramachandran S, Willenberg BJ, Adams AB, Hering BJ, Graham ML. Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates. FRONTIERS IN TRANSPLANTATION 2024; 3:1352777. [PMID: 38993753 PMCID: PMC11235263 DOI: 10.3389/frtra.2024.1352777] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 01/09/2024] [Indexed: 07/13/2024]
Abstract
Introduction Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability. Methods Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology. Results Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection. Discussion The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.
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Affiliation(s)
- David J. Leishman
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Scott H. Oppler
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Laura L. Hocum Stone
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Timothy D. O’Brien
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States
| | - Sabarinathan Ramachandran
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Bradley J. Willenberg
- Department of Internal Medicine, University of Central Florida College of Medicine, Orlando, FL, United States
| | - Andrew B. Adams
- Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Bernhard J. Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Melanie L. Graham
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States
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Samadi A, Moammeri A, Pourmadadi M, Abbasi P, Hosseinpour Z, Farokh A, Shamsabadipour A, Heydari M, Mohammadi MR. Cell Encapsulation and 3D Bioprinting for Therapeutic Cell Transplantation. ACS Biomater Sci Eng 2023; 9:1862-1890. [PMID: 36877212 DOI: 10.1021/acsbiomaterials.2c01183] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
The promise of cell therapy has been augmented by introducing biomaterials, where intricate scaffold shapes are fabricated to accommodate the cells within. In this review, we first discuss cell encapsulation and the promising potential of biomaterials to overcome challenges associated with cell therapy, particularly cellular function and longevity. More specifically, cell therapies in the context of autoimmune disorders, neurodegenerative diseases, and cancer are reviewed from the perspectives of preclinical findings as well as available clinical data. Next, techniques to fabricate cell-biomaterials constructs, focusing on emerging 3D bioprinting technologies, will be reviewed. 3D bioprinting is an advancing field that enables fabricating complex, interconnected, and consistent cell-based constructs capable of scaling up highly reproducible cell-biomaterials platforms with high precision. It is expected that 3D bioprinting devices will expand and become more precise, scalable, and appropriate for clinical manufacturing. Rather than one printer fits all, seeing more application-specific printer types, such as a bioprinter for bone tissue fabrication, which would be different from a bioprinter for skin tissue fabrication, is anticipated in the future.
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Affiliation(s)
- Amirmasoud Samadi
- Department of Chemical and Biomolecular Engineering, 6000 Interdisciplinary Science & Engineering Building (ISEB), Irvine, California 92617, United States
| | - Ali Moammeri
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Mehrab Pourmadadi
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Parisa Abbasi
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Azadi Avenue, Tehran 1458889694, Iran
| | - Zeinab Hosseinpour
- Biotechnology Research Laboratory, Faculty of Chemical Engineering, Babol Noshirvani University of Technology, Babol 4714871167, Mazandaran Province, Iran
| | - Arian Farokh
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Amin Shamsabadipour
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Maryam Heydari
- Department of Cell and Molecular Biology, Faculty of Biological Science, University of Kharazmi, Tehran 199389373, Iran
| | - M Rezaa Mohammadi
- Dale E. and Sarah Ann Fowler School of Engineering, Chapman University, Orange, California 92866, United States
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Roep BO. The need and benefit of immune monitoring to define patient and disease heterogeneity, mechanisms of therapeutic action and efficacy of intervention therapy for precision medicine in type 1 diabetes. Front Immunol 2023; 14:1112858. [PMID: 36733487 PMCID: PMC9887285 DOI: 10.3389/fimmu.2023.1112858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
The current standard of care for type 1 diabetes patients is limited to treatment of the symptoms of the disease, insulin insufficiency and its complications, not its cause. Given the autoimmune nature of type 1 diabetes, immunology is critical to understand the mechanism of disease progression, patient and disease heterogeneity and therapeutic action. Immune monitoring offers the key to all this essential knowledge and is therefore indispensable, despite the challenges and costs associated. In this perspective, I attempt to make this case by providing evidence from the past to create a perspective for future trials and patient selection.
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Narayan G, Ronima K R, Thummer RP. Direct Reprogramming of Somatic Cells into Induced β-Cells: An Overview. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1410:171-189. [PMID: 36515866 DOI: 10.1007/5584_2022_756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The persistent shortage of insulin-producing islet mass or β-cells for transplantation in the ever-growing diabetic population worldwide is a matter of concern. To date, permanent cure to this medical complication is not available and soon after the establishment of lineage-specific reprogramming, direct β-cell reprogramming became a viable alternative for β-cell regeneration. Direct reprogramming is a straightforward and powerful technique that can provide an unlimited supply of cells by transdifferentiating terminally differentiated cells toward the desired cell type. This approach has been extensively used by multiple groups to reprogram non-β-cells toward insulin-producing β-cells. The β-cell identity has been achieved by various studies via ectopic expression of one or more pancreatic-specific transcription factors in somatic cells, bypassing the pluripotent state. This work highlights the importance of the direct reprogramming approaches (both integrative and non-integrative) in generating autologous β-cells for various applications. An in-depth understanding of the strategies and cell sources could prove beneficial for the efficient generation of integration-free functional insulin-producing β-cells for diabetic patients lacking endogenous β-cells.
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Affiliation(s)
- Gloria Narayan
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Ronima K R
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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Berney T, Wassmer CH, Lebreton F, Bellofatto K, Fonseca LM, Bignard J, Hanna R, Peloso A, Berishvili E. From islet of Langerhans transplantation to the bioartificial pancreas. Presse Med 2022; 51:104139. [PMID: 36202182 DOI: 10.1016/j.lpm.2022.104139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity. A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage. This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress.
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Affiliation(s)
- Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland; Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland; Department of Surgery, School of Medicine and Natural Sciences, Ilia State University, Tbilisi, Georgia
| | - Charles H Wassmer
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Kevin Bellofatto
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Laura Mar Fonseca
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Juliette Bignard
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Reine Hanna
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Andrea Peloso
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland; Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia.
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9
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den Hollander NHM, Roep BO. From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes. Front Med (Lausanne) 2022; 9:932086. [PMID: 35903316 PMCID: PMC9314738 DOI: 10.3389/fmed.2022.932086] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/13/2022] [Indexed: 12/12/2022] Open
Abstract
Type 1 diabetes (T1D) remains a devastating disease that requires much effort to control. Life-long daily insulin injections or an insulin pump are required to avoid severe complications. With many factors contributing to disease onset, T1D is a complex disease to cure. In this review, the risk factors, pathophysiology and defect pathways are discussed. Results from (pre)clinical studies are highlighted that explore restoration of insulin production and reduction of autoimmunity. It has become clear that treatment responsiveness depends on certain pathophysiological or genetic characteristics that differ between patients. For instance, age at disease manifestation associated with efficacy of immune intervention therapies, such as depleting islet-specific effector T cells or memory B cells and increasing immune regulation. The new challenge is to determine in whom to apply which intervention strategy. Within patients with high rates of insulitis in early T1D onset, therapy depleting T cells or targeting B lymphocytes may have a benefit, whereas slow progressing T1D in adults may be better served with more sophisticated, precise and specific disease modifying therapies. Genetic barcoding and immune profiling may help determining from which new T1D endotypes patients suffer. Furthermore, progressed T1D needs replenishment of insulin production besides autoimmunity reversal, as too many beta cells are already lost or defect. Recurrent islet autoimmunity and allograft rejection or necrosis seem to be the most challenging obstacles. Since beta cells are highly immunogenic under stress, treatment might be more effective with stress reducing agents such as glucagon-like peptide 1 (GLP-1) analogs. Moreover, genetic editing by CRISPR-Cas9 allows to create hypoimmunogenic beta cells with modified human leukocyte antigen (HLA) expression that secrete immune regulating molecules. Given the differences in T1D between patients, stratification of endotypes in clinical trials seems essential for precision medicines and clinical decision making.
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Affiliation(s)
- Nicoline H M den Hollander
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.,Graduate School, Utrecht University, Utrecht, Netherlands
| | - Bart O Roep
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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10
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Lei J, Zhang A, Deng H, Yang Z, Peters CW, Lee KM, Wang Z, Rosales IA, Rickert C, Markmann JF. Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate. Am J Transplant 2022; 22:966-972. [PMID: 34704352 PMCID: PMC8897220 DOI: 10.1111/ajt.16875] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/03/2021] [Accepted: 10/18/2021] [Indexed: 01/25/2023]
Abstract
Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP. Robust glycemic control and graft survival were achieved for the planned study period of >90 days. Our observations suggest the intrapleural space provides an attractive locale for islet transplantation due to its higher oxygen tension, ability to accommodate large transplant tissue volumes, and a lack of IBMIR-mediated islet damage. Our preliminary results reveal the promise of the intrapleural space as an alternative site for clinical islet transplantation in the treatment of type 1 diabetes.
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Affiliation(s)
- Ji Lei
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA,To whom correspondence should be addressed: Ji Lei, MD, MBA, 185 Cambridge Street, Rm3836, Massachusetts General Hospital, Boston, MA 02114. Phone: 617-643-5327, FAX: 617-643-7464,
| | - Alexander Zhang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Hongping Deng
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Zhihong Yang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Cole W. Peters
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Kang M. Lee
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Zhenjuan Wang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Charles Rickert
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - James F. Markmann
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
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11
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Wassmer CH, Lebreton F, Bellofatto K, Perez L, Cottet-Dumoulin D, Andres A, Bosco D, Berney T, Othenin-Girard V, Martinez De Tejada B, Cohen M, Olgasi C, Follenzi A, Berishvili E. Bio-Engineering of Pre-Vascularized Islet Organoids for the Treatment of Type 1 Diabetes. Transpl Int 2022; 35:10214. [PMID: 35185372 PMCID: PMC8842259 DOI: 10.3389/ti.2021.10214] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/08/2021] [Indexed: 12/13/2022]
Abstract
Lack of rapid revascularization and inflammatory attacks at the site of transplantation contribute to impaired islet engraftment and suboptimal metabolic control after clinical islet transplantation. In order to overcome these limitations and enhance engraftment and revascularization, we have generated and transplanted pre-vascularized insulin-secreting organoids composed of rat islet cells, human amniotic epithelial cells (hAECs), and human umbilical vein endothelial cells (HUVECs). Our study demonstrates that pre-vascularized islet organoids exhibit enhanced in vitro function compared to native islets, and, most importantly, better engraftment and improved vascularization in vivo in a murine model. This is mainly due to cross-talk between hAECs, HUVECs and islet cells, mediated by the upregulation of genes promoting angiogenesis (vegf-a) and β cell function (glp-1r, pdx1). The possibility of adding a selected source of endothelial cells for the neo-vascularization of insulin-scereting grafts may also allow implementation of β cell replacement therapies in more favourable transplantation sites than the liver.
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Affiliation(s)
- Charles-Henri Wassmer
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Fanny Lebreton
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Kevin Bellofatto
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Lisa Perez
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - David Cottet-Dumoulin
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Axel Andres
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Domenico Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Thierry Berney
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Véronique Othenin-Girard
- Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Begoña Martinez De Tejada
- Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Marie Cohen
- Department of Pediatrics, Gynecology and Obstetrics, Faculty of Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Christina Olgasi
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Antonia Follenzi
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Ekaterine Berishvili
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
- Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia
- *Correspondence: Ekaterine Berishvili,
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12
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Jia J, Kang Q, Liu S, Song Y, Wong FS, Qiu Y, Li M. Artemether and aspterric acid induce pancreatic α cells to transdifferentiate into β cells in zebrafish. Br J Pharmacol 2021; 179:1962-1977. [PMID: 34871457 DOI: 10.1111/bph.15769] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 11/12/2021] [Accepted: 11/24/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND AND PURPOSE Recently, the anti-malarial drug, artemether, and the neurotransmitter γ-aminobutyric acid (GABA) were identified to convert α cells into β-like cells in vivo. However, some of these observations were challenged by other studies. To help address the controversy, we took advantage of zebrafish as a model to perform this study. EXPERIMENTAL APPROACH Firstly, we performed a small molecule screening for artemether and its skeleton analogs. Secondly, we used the Cre-LoxP system for lineage tracing to indicate the conversion of α cells into β cells in vivo. The stable transgenic ins2:eGFP αTC1-6 cell line were used for evaluation of α cell transdifferentiation in vitro. We further used multiple zebrafish transgenic and mutation lines to demonstrate β-cell differentiation, β-cell ablation and α-cell hyperplasia in this study. KEY RESULTS We showed that artemether and another sesquiterpene, aspterric acid, induced α cell transdifferentiation into β cells, both in zebrafish as well as using αTC1-6 cells. Furthermore, these two compounds also converted α cells into β cells when β cells were lost or α cells were hyperplastic in zebrafish. Unlike the previous report, the conversion of α cells to β cells was mediated by increasing Pax4 expression, but not suppression of Arx expression. CONCLUSIONS AND IMPLICATIONS Our data suggest that in zebrafish and αTC1-6 cells, both artemether and aspterric acid induce α cell transdifferentiation. Our data, along with those of Li et al. (2017), suggested that artemether and aspterric acid were able to induce α cell transdifferentiation, at least in zebrafish and αTC1-6 cells.
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Affiliation(s)
- Jianxin Jia
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.,State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Qi Kang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.,State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Shunzhi Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yabin Song
- Department of Neurology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China
| | - F Susan Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Yingkun Qiu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Mingyu Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.,Department of Otolaryngology Head and Neck Surgery, School of Medicine, Xiamen University
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13
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Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device. Pharmaceutics 2021; 13:pharmaceutics13122077. [PMID: 34959358 PMCID: PMC8704798 DOI: 10.3390/pharmaceutics13122077] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 11/17/2022] Open
Abstract
Macroencapsulation systems have been developed to improve islet cell transplantation but can induce a foreign body response (FBR). The development of neovascularization adjacent to the device is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previously we developed additive manufactured multi-scale porosity implants, which demonstrated a 2.5-fold increase in tissue vascularity and integration surrounding the implant when compared to a non-textured implant. In parallel to this, we have developed poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymer microspheres containing VEGF, which exhibited continued release of bioactive VEGF for 4-weeks in vitro. In the present study, we describe the next step towards clinical implementation of an islet macroencapsulation device by combining a multi-scale porosity device with VEGF releasing microspheres in a rodent model to assess prevascularization over a 4-week period. An in vivo estimation of vascular volume showed a significant increase in vascularity (* p = 0.0132) surrounding the +VEGF vs. −VEGF devices, however, histological assessment of blood vessels per area revealed no significant difference. Further histological analysis revealed significant increases in blood vessel stability and maturity (** p = 0.0040) and vessel diameter size (*** p = 0.0002) surrounding the +VEGF devices. We also demonstrate that the addition of VEGF microspheres did not cause a heightened FBR. In conclusion, we demonstrate that the combination of VEGF microspheres with our multi-scale porous macroencapsulation device, can encourage the formation of significantly larger, stable, and mature blood vessels without exacerbating the FBR.
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14
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Kenyon NS, Willman MA, Han D, Leeman RS, Rabassa A, Diaz WL, Geary JC, Poumian-Ruiz E, Griswold AJ, Van Booven DJ, Thompson R, Ordoukhanian P, Head SR, Kenyon NM, McHenry KG, Salomon DR, Bartholomew AM, Berman DM. Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing. Am J Transplant 2021; 21:3524-3537. [PMID: 34008325 PMCID: PMC9034438 DOI: 10.1111/ajt.16693] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/23/2021] [Accepted: 05/06/2021] [Indexed: 01/25/2023]
Abstract
Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co-transplant of MSC and islets on post-operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third-party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti-donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.
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Affiliation(s)
- Norma S. Kenyon
- Diabetes Research Institute, University of Miami, Miami, Florida, USA,Department of Surgery, University of Miami, Miami, Florida, USA,Department of Microbiology and Immunology, University of Miami, Miami, Florida, USA,Department of Biomedical Engineering, University of Miami, Miami, Florida, USA
| | | | - Dongmei Han
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Rachel S. Leeman
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Alex Rabassa
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Waldo L. Diaz
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - James C. Geary
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Ena Poumian-Ruiz
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Anthony J. Griswold
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA,The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA
| | - Derek J. Van Booven
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA
| | - Ryan Thompson
- The Scripps Research Institute, La Jolla, California, USA
| | - Philip Ordoukhanian
- The Scripps Research Institute, La Jolla, California, USA,The Scripps Research Institute Genomics Core Facility, La Jolla, California, USA
| | - Steven R. Head
- The Scripps Research Institute, La Jolla, California, USA,The Scripps Research Institute Genomics Core Facility, La Jolla, California, USA
| | - Norman M. Kenyon
- Diabetes Research Institute, University of Miami, Miami, Florida, USA,Department of Surgery, University of Miami, Miami, Florida, USA
| | - Kenton G. McHenry
- National Center for Supercomputing Applications, University of Illinois, Urbana-Champaign, Chicago, Illinois, USA
| | | | | | - Dora M. Berman
- Diabetes Research Institute, University of Miami, Miami, Florida, USA,Department of Surgery, University of Miami, Miami, Florida, USA
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15
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Samojlik MM, Stabler CL. Designing biomaterials for the modulation of allogeneic and autoimmune responses to cellular implants in Type 1 Diabetes. Acta Biomater 2021; 133:87-101. [PMID: 34102338 PMCID: PMC9148663 DOI: 10.1016/j.actbio.2021.05.039] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/05/2021] [Accepted: 05/20/2021] [Indexed: 12/15/2022]
Abstract
The effective suppression of adaptive immune responses is essential for the success of allogeneic cell therapies. In islet transplantation for Type 1 Diabetes, pre-existing autoimmunity provides an additional hurdle, as memory autoimmune T cells mediate both an autoantigen-specific attack on the donor beta cells and an alloantigen-specific attack on the donor graft cells. Immunosuppressive agents used for islet transplantation are generally successful in suppressing alloimmune responses, but dramatically hinder the widespread adoption of this therapeutic approach and fail to control memory T cell populations, which leaves the graft vulnerable to destruction. In this review, we highlight the capacity of biomaterials to provide local and nuanced instruction to suppress or alter immune pathways activated in response to an allogeneic islet transplant. Biomaterial immunoisolation is a common approach employed to block direct antigen recognition and downstream cell-mediated graft destruction; however, immunoisolation alone still permits shed donor antigens to escape into the host environment, resulting in indirect antigen recognition, immune cell activation, and the creation of a toxic graft site. Designing materials to decrease antigen escape, improve cell viability, and increase material compatibility are all approaches that can decrease the local release of antigen and danger signals into the implant microenvironment. Implant materials can be further enhanced through the local delivery of anti-inflammatory, suppressive, chemotactic, and/or tolerogenic agents, which serve to control both the innate and adaptive immune responses to the implant with a benefit of reduced systemic effects. Lessons learned from understanding how to manipulate allogeneic and autogenic immune responses to pancreatic islets can also be applied to other cell therapies to improve their efficacy and duration. STATEMENT OF SIGNIFICANCE: This review explores key immunologic concepts and critical pathways mediating graft rejection in Type 1 Diabetes, which can instruct the future purposeful design of immunomodulatory biomaterials for cell therapy. A summary of immunological pathways initiated following cellular implantation, as well as current systemic immunomodulatory agents used, is provided. We then outline the potential of biomaterials to modulate these responses. The capacity of polymeric encapsulation to block some powerful rejection pathways is covered. We also highlight the role of cellular health and biocompatibility in mitigating immune responses. Finally, we review the use of bioactive materials to proactively modulate local immune responses, focusing on key concepts of anti-inflammatory, suppressive, and tolerogenic agents.
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Affiliation(s)
- Magdalena M Samojlik
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Cherie L Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA; University of Florida Diabetes Institute, Gainesville, FL, USA; Graduate Program in Biomedical Sciences, College of Medicine, University of Florida, Gainesville, FL, USA.
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16
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Qu Z, Lou Q, Cooper DKC, Pu Z, Lu Y, Chen J, Ni Y, Zhan Y, Chen J, Li Z, Zhan N, Zeng Y, Tu Z, Cao H, Dai Y, Cai Z, Mou L. Potential roles of mesenchymal stromal cells in islet allo- and xenotransplantation for type 1 diabetes mellitus. Xenotransplantation 2021; 28:e12678. [PMID: 33569837 DOI: 10.1111/xen.12678] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 01/05/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022]
Abstract
Islet transplantation is poised to play an important role in the treatment of type 1 diabetes mellitus (T1DM). However, there are several challenges limiting its widespread use, including the instant blood-mediated inflammatory reaction, hypoxic/ischemic injury, and the immune response. Mesenchymal stem/stromal cells (MSCs) are known to exert regenerative, immunoregulatory, angiogenic, and metabolic properties. Here, we review recent reports on the application of MSCs in islet allo- and xenotransplantation. We also document the clinical trials that have been undertaken or are currently underway, relating to the co-transplantation of islets and MSCs. Increasing evidence indicates that co-transplantation of MSCs prolongs islet graft survival by locally secreted protective factors that reduce immune reactivity and promote vascularization, cell survival, and regeneration. MSC therapy may be a promising option for islet transplantation in patients with T1DM.
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Affiliation(s)
- Zepeng Qu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Qi Lou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.,Shenzhen Lansi Institute of Artificial Intelligence in Medicine, Shenzhen, China
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zuhui Pu
- Department of Radiology, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Ying Lu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jiao Chen
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yong Ni
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yongqiang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jun Chen
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Zhenjie Li
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Naiyang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yi Zeng
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Ziwei Tu
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Huayi Cao
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
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17
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Zirpel H, Roep BO. Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot's Print. Front Endocrinol (Lausanne) 2021; 12:666795. [PMID: 33912139 PMCID: PMC8072455 DOI: 10.3389/fendo.2021.666795] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/08/2021] [Indexed: 12/12/2022] Open
Abstract
The classical view of type 1 diabetes assumes that the autoimmune mediated targeting of insulin producing ß-cells is caused by an error of the immune system. Malfunction and stress of beta cells added the target tissue at the center of action. The innate immune system, and in particular islet-resident cells of the myeloid lineage, could function as a link between stressed ß-cells and activation and recognition by the adaptive immune system. We survey the role of islet-resident macrophages and dendritic cells in healthy islet homeostasis and pathophysiology of T1D. Knowledge of islet-resident antigen presenting cells in rodents is substantial, but quite scarce in humans, in particular regarding dendritic cells. Differences in blood between healthy and diseased individuals were reported, but it remains elusive to what extend these contribute to T1D onset. Increasing our understanding of the interaction between ß-cells and innate immune cells may provide new insights into disease initiation and development that could ultimately point to future treatment options. Here we review current knowledge of islet-resident macrophages and dendritic cells, place these in context of current clinical trials, and guide future research.
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18
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Yao Q, Chen R, Ganapathy V, Kou L. Therapeutic application and construction of bilirubin incorporated nanoparticles. J Control Release 2020; 328:407-424. [DOI: 10.1016/j.jconrel.2020.08.054] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023]
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19
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Hu M, Cherkaoui I, Misra S, Rutter GA. Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research. Front Endocrinol (Lausanne) 2020; 11:576632. [PMID: 33162936 PMCID: PMC7580382 DOI: 10.3389/fendo.2020.576632] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/17/2020] [Indexed: 12/13/2022] Open
Abstract
The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for β cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.
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Affiliation(s)
- Ming Hu
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Ines Cherkaoui
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Shivani Misra
- Metabolic Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, United Kingdom
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20
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Berney T, Berishvili E. I've got you under my skin. Nat Metab 2020; 2:993-994. [PMID: 32895575 DOI: 10.1038/s42255-020-0268-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland.
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland.
- Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland.
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland
- Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia
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21
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Wang JK, Cheam NMJ, Irvine SA, Tan NS, Venkatraman S, Tay CY. Interpenetrating Network of Alginate–Human Adipose Extracellular Matrix Hydrogel for Islet Cells Encapsulation. Macromol Rapid Commun 2020; 41:e2000275. [DOI: 10.1002/marc.202000275] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 08/04/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Jun Kit Wang
- School of Materials Science and Engineering Nanyang Technological University Singapore N4.1, 50 Nanyang Avenue Singapore 639798 Singapore
| | - Nicole Mein Ji Cheam
- School of Materials Science and Engineering Nanyang Technological University Singapore N4.1, 50 Nanyang Avenue Singapore 639798 Singapore
| | - Scott Alexander Irvine
- School of Materials Science and Engineering Nanyang Technological University Singapore N4.1, 50 Nanyang Avenue Singapore 639798 Singapore
| | - Nguan Soon Tan
- School of Biological Sciences Nanyang Technological University Singapore 60 Nanyang Drive Singapore 637551 Singapore
- Lee Kong Chian School of Medicine Nanyang Technological University Singapore 11 Mandalay Road Singapore 308232 Singapore
| | - Subbu Venkatraman
- Department of Materials Science and Engineering National University of Singapore Blk EA, 9 Engineering Drive 1 Singapore 117575 Singapore
| | - Chor Yong Tay
- School of Materials Science and Engineering Nanyang Technological University Singapore N4.1, 50 Nanyang Avenue Singapore 639798 Singapore
- School of Biological Sciences Nanyang Technological University Singapore 60 Nanyang Drive Singapore 637551 Singapore
- Environmental Chemistry and Materials Centre Nanyang Environment and Water Research Institute 1 CleanTech Loop, CleanTech One Singapore 637141 Singapore
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22
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Grafting Islets to a Dissected Peritoneal Pouch to Improve Transplant Survival and Function. Transplantation 2020; 104:2307-2316. [PMID: 32541557 DOI: 10.1097/tp.0000000000003355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Although the liver is the primary site for clinical islet transplantation, it poses several restrictions, especially limited tissue volume due to portal vein pressure. We evaluated the preperitoneal space as an extrahepatic islet transplant site to deliver high tissue volumes and sustain long-term graft function. METHODS A peritoneal pouch was formed by dissecting the parietal peritoneum from the transversalis fascia of mice. Syngeneic C57BL/6 donor islets were transplanted into the peritoneal pouch of diabetic mouse recipients. Blood glucose was monitored for islet function, and miR-375 was analyzed for islet damage. Islet graft morphology and vascularization were evaluated by immunohistochemistry. [F] fluoro-D-glucose positron emission tomography/computed tomography was used to image islet grafts. RESULTS Transplantation of 300 syngeneic islets into the peritoneal pouch of recipients reversed hyperglycemia for >60 days. Serum miR-375 was significantly lower in the peritoneal pouch group than in the peritoneal cavity group. Peritoneal pouch islet grafts showed high neovascularization and sustained insulin and glucagon expression up to 80 days posttransplantation. A peritoneal pouch graft with high tissue volume (1000 islets) could be visualized by positron emission tomography/computed tomography imaging. Human islets transplanted into the peritoneal pouch of diabetic nude mice also reversed hyperglycemia successfully. CONCLUSIONS Islets transplanted into a dissected peritoneal pouch show high efficiency to reverse diabetes and sustain islet graft function. The preperitoneal site has the advantages of capacity for high tissue volume, enriched revascularization and minimal inflammatory damage. It can also serve as an extrahepatic site for transplanting large volume of islets necessitated in islet autotransplantation.
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23
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Lebreton F, Bellofatto K, Wassmer CH, Perez L, Lavallard V, Parnaud G, Cottet-Dumoulin D, Kerr-Conte J, Pattou F, Bosco D, Othenin-Girard V, Martinez de Tejada B, Berishvili E. Shielding islets with human amniotic epithelial cells enhances islet engraftment and revascularization in a murine diabetes model. Am J Transplant 2020; 20:1551-1561. [PMID: 32031745 DOI: 10.1111/ajt.15812] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/12/2020] [Accepted: 01/28/2020] [Indexed: 01/25/2023]
Abstract
Hypoxia is a major cause of considerable islet loss during the early posttransplant period. Here, we investigate whether shielding islets with human amniotic epithelial cells (hAECs), which possess anti-inflammatory and regenerative properties, improves islet engraftment and survival. Shielded islets were generated on agarose microwells by mixing rat islets (RIs) or human islets (HI) and hAECs (100 hAECs/IEQ). Islet secretory function and viability were assessed after culture in hypoxia (1% O2 ) or normoxia (21% O2 ) in vitro. In vivo function was evaluated after transplant under the kidney capsule of diabetic immunodeficient mice. Graft morphology and vascularization were evaluated by immunohistochemistry. Both shielded RIs and HIs show higher viability and increased glucose-stimulated insulin secretion after exposure to hypoxia in vitro compared with control islets. Transplant of shielded islets results in considerably earlier normoglycemia and vascularization, an enhanced glucose tolerance, and a higher β cell mass. Our results show that hAECs have a clear cytoprotective effect against hypoxic damages in vitro. This strategy improves β cell mass engraftment and islet revascularization, leading to an improved capacity of islets to reverse hyperglycemia, and could be rapidly applicable in the clinical situation seeing that the modification to HIs are minor.
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Affiliation(s)
- Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Kevin Bellofatto
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Charles H Wassmer
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Lisa Perez
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Géraldine Parnaud
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - David Cottet-Dumoulin
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Julie Kerr-Conte
- INSERM U1190, Translational Research for Diabetes, University of Lille, France
| | - François Pattou
- INSERM U1190, Translational Research for Diabetes, University of Lille, France
| | - Domenico Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Véronique Othenin-Girard
- Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland
| | - Begoña Martinez de Tejada
- Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Institute of Medical Research, Ilia State University, Tbilisi, Georgia
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24
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Affiliation(s)
- Bart O Roep
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute at the Beckman Research Institute, City of Hope National Medical Center, Duarte, CA .,Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
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25
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Delcassian D, Luzhansky I, Spanoudaki V, Bochenek M, McGladrigan C, Nguyen A, Norcross S, Zhu Y, Shan CS, Hausser R, Shakesheff KM, Langer R, Anderson DG. Magnetic Retrieval of Encapsulated Beta Cell Transplants from Diabetic Mice Using Dual-Function MRI Visible and Retrievable Microcapsules. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1904502. [PMID: 32134138 DOI: 10.1002/adma.201904502] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 12/03/2019] [Indexed: 05/18/2023]
Abstract
Encapsulated beta cell transplantation offers a potential cure for a subset of diabetic patients. Once transplanted, beta cell grafts can help to restore glycemic control; however, locating and retrieving cells in the event of graft failure may pose a surgical challenge. Here, a dual-function nanoparticle-loaded hydrogel microcapsule is developed that enables graft retrieval under an applied magnetic field. Additionally, this system facilitates graft localization via magnetic resonance imaging (MRI), and graft isolation from the immune system. Iron oxide nanoparticles encapsulated within alginate hydrogel capsules containing viable islets are transplanted and the in vitro and in vivo retrieval of capsules containing nanoparticles functionalized with various ligands are compared. Capsules containing islets co-encapsulated with COOH-coated nanoparticles restore normal glycemia in immunocompetent diabetic mice for at least 6 weeks, can be visualized using MRI, and are retrievable in a magnetic field. Application of a magnetic field for 90 s via a magnetically assisted retrieval device facilitates rapid retrieval of up to 94% (±3.1%) of the transplant volume 24 h after surgical implantation. This strategy aids monitoring of cell-capsule locations in vivo, facilitates graft removal at the end of the transplant lifetime, and may be applicable to many encapsulated cell transplant systems.
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Affiliation(s)
- Derfogail Delcassian
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Division of Regenerative Medicine and Cellular Therapies, University of Nottingham, Nottingham, NG7 2RD, UK
| | - Igor Luzhansky
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Virginia Spanoudaki
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Matthew Bochenek
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Collin McGladrigan
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Amy Nguyen
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Samuel Norcross
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Yuhan Zhu
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Crystal Shuo Shan
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Reed Hausser
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Kevin M Shakesheff
- Division of Regenerative Medicine and Cellular Therapies, University of Nottingham, Nottingham, NG7 2RD, UK
| | - Robert Langer
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA
- Howard Hughes Medical Institute, Harvard University, Cambridge, MA, 02138, USA
- Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA
| | - Daniel G Anderson
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA
- Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA
- Howard Hughes Medical Institute, Harvard University, Cambridge, MA, 02138, USA
- Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA
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26
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Niu M, Liu Y, Xiang L, Zhao Y, Yuan J, Jia Y, Dai X, Chen H. Long-term case study of a Wuzhishan miniature pig with diabetes. Animal Model Exp Med 2020; 3:22-31. [PMID: 32318656 PMCID: PMC7167240 DOI: 10.1002/ame2.12098] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 11/28/2019] [Accepted: 12/11/2019] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Miniature pigs are attractive animal models for exploring diabetes because they are similar to humans in terms of physiological structure and metabolism. However, little is known about the complications of diabetes in pigs. METHODS In this study, a 28-month observation of a Wuzhishan miniature pig with streptozotocin (STZ)-induced (120 mg/kg) diabetes was conducted, to investigate diabetes-related complications and the possibility of self-recovery in miniature pigs. Blood glucose, serum and urinary biochemistry was measured, and histopathologic examinations of eyes, kidney and pancreas were made. RESULTS During the observation, diabetic complications of eyes and kidney were observed. The eye complications included bilateral cataracts in the 15th month and degeneration of inner retina and microaneurysm in the 28th month. Kidney complications included glomerular mesangial expansion, focal segmental glomerular sclerosis, and renal tubular epithelial degeneration, but no proteinuria was observed. By 28 months after the application of STZ, with no treatment given, blood glucose had recovered and the number of pancreatic islet beta-cells had increased significantly. CONCLUSIONS We showed that the STZ-induced diabetes model in miniature pigs could accurately mimic the pathological changes of human diabetes, and that pancreatic islet beta-cell regeneration did occur in an adult miniature pig, providing a new means for exploring diabetic complications and pancreatic islet beta-cell regeneration.
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Affiliation(s)
- Miaomiao Niu
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Yaqian Liu
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Lei Xiang
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Yuqiong Zhao
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Jifang Yuan
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Yunxiao Jia
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Xin Dai
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
| | - Hua Chen
- Laboratory Animal CenterChinese PLA General HospitalBeijingPR China
- State Key Laboratory of Kidney DiseasesChinese PLA General HospitalBeijingPR China
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Espona-Noguera A, Ciriza J, Cañibano-Hernández A, Orive G, Hernández RM, Saenz del Burgo L, Pedraz JL. Review of Advanced Hydrogel-Based Cell Encapsulation Systems for Insulin Delivery in Type 1 Diabetes Mellitus. Pharmaceutics 2019; 11:E597. [PMID: 31726670 PMCID: PMC6920807 DOI: 10.3390/pharmaceutics11110597] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/11/2022] Open
Abstract
: Type 1 Diabetes Mellitus (T1DM) is characterized by the autoimmune destruction of β-cells in the pancreatic islets. In this regard, islet transplantation aims for the replacement of the damaged β-cells through minimally invasive surgical procedures, thereby being the most suitable strategy to cure T1DM. Unfortunately, this procedure still has limitations for its widespread clinical application, including the need for long-term immunosuppression, the lack of pancreas donors and the loss of a large percentage of islets after transplantation. To overcome the aforementioned issues, islets can be encapsulated within hydrogel-like biomaterials to diminish the loss of islets, to protect the islets resulting in a reduction or elimination of immunosuppression and to enable the use of other insulin-producing cell sources. This review aims to provide an update on the different hydrogel-based encapsulation strategies of insulin-producing cells, highlighting the advantages and drawbacks for a successful clinical application.
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Affiliation(s)
- Albert Espona-Noguera
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Jesús Ciriza
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Alberto Cañibano-Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
- University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01006 Vitoria, Spain
- Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore
| | - Rosa María Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Laura Saenz del Burgo
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
| | - Jose Luis Pedraz
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (A.E.-N.); (J.C.); (A.C.-H.); (R.M.H.)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain
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Staels W, Heremans Y, Heimberg H, De Leu N. VEGF-A and blood vessels: a beta cell perspective. Diabetologia 2019; 62:1961-1968. [PMID: 31414144 DOI: 10.1007/s00125-019-4969-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 06/11/2019] [Indexed: 02/07/2023]
Abstract
Reciprocal signalling between the endothelium and the pancreatic epithelium is crucial for coordinated differentiation of the embryonic endocrine and exocrine pancreas. In the adult pancreas, islets depend on their dense capillary network to adequately respond to changes in plasma glucose levels. Vascular changes contribute to the onset and progression of both type 1 and type 2 diabetes. Impaired revascularisation of islets transplanted in individuals with type 1 diabetes is linked to islet graft failure and graft loss. This review summarises our understanding of the role of vascular endothelial growth factor-A (VEGF-A) and endothelial cells in beta cell development, physiology and disease. In addition, the therapeutic potential of modulating VEGF-A levels in beta and beta-like cells for transplantation is discussed.
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Affiliation(s)
- Willem Staels
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Institut Cochin, CNRS, INSERM, Université de Paris, F-75014, Paris, France
| | - Yves Heremans
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Nico De Leu
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Department of Endocrinology, UZ Brussel, Brussels, Belgium.
- Department of Endocrinology, ASZ Aalst, Aalst, Belgium.
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Pathak S, Pham TT, Jeong JH, Byun Y. Immunoisolation of pancreatic islets via thin-layer surface modification. J Control Release 2019; 305:176-193. [DOI: 10.1016/j.jconrel.2019.04.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/15/2019] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
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30
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31
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The Optimization of the Prevascularization Procedures for Improving Subcutaneous Islet Engraftment. Transplantation 2018; 102:387-395. [PMID: 29019814 DOI: 10.1097/tp.0000000000001970] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Subcutaneous islet transplantation is associated with minimal invasiveness, but poor vascularization. Thus, the optimization of the prevascularization procedures is crucial for improving the outcomes. Although the effectiveness of basic fibroblast growth factor (bFGF) was reported, the optimal procedures remain unclear. We sought to optimize the prevascularization procedures including the use of a novel scaffold, recombinant peptide (RCP). METHODS Devices containing various amount of bFGF with/without heparin or RCP were implanted into the subcutaneous space of diabetic C57BL/6 mice. Syngeneic islets were transplanted into the prevascularized space. Blood glucose, intraperitoneal glucose tolerance, and immunohistochemistry were evaluated. RESULTS The cure rates in all the device groups irrespective of bFGF doses were considerably higher than in the nondevice group. The cure rate in the bFGF0 group was unexpectedly higher than that in the subcutaneous islet transplant alone group (the None group) (57.1% vs 28.6%). Glucose tolerance was ameliorated in the bFGF10(-), 10(+) and 15(-) groups. The number of von Willebrand factor-positive vessels in the bFGF10(+) group was significantly higher than that in the None and bFGF0 groups (P < 0.01). Taken together, the bFGF10(+) group was considered to have received optimized procedures. In a marginal graft model, the efficiency in the RCP group was better than that in the bFGF10(+) group, furthermore, comparable to that in the intraportal transplantation group. Unlike bFGF, no bleeding and effusion were observed in the RCP group. CONCLUSIONS These results suggest that optimizing biomaterials to induce efficient prevascularization could be a novel strategy for improving subcutaneous islet transplantation.
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Delaune V, Lacotte S, Gex Q, Slits F, Kahler-Quesada A, Lavallard V, Peloso A, Orci LA, Berney T, Toso C. Effects of remote ischaemic preconditioning on intraportal islet transplantation in a rat model. Transpl Int 2018; 32:323-333. [PMID: 30318858 DOI: 10.1111/tri.13360] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 07/23/2018] [Accepted: 10/08/2018] [Indexed: 12/29/2022]
Abstract
Remote ischaemic preconditioning (RIPC), which is the intermittent interruption of blood flow to a site distant from the target organ, is known to improve solid organ resistance to ischaemia-reperfusion injury. This procedure could be of interest in islet transplantation to mitigate hypoxia-related loss of islet mass after isolation and transplantation. Islets isolated from control or RIPC donors were analyzed for yield, metabolic activity, gene expression and high mobility group box-1 (HMGB1) content. Syngeneic marginal mass transplantation was performed in four streptozotocin-induced diabetic groups: control, RIPC in donor only, RIPC in recipient only, and RIPC in donor and recipient. Islets isolated from RIPC donors had an increased yield of 20% after 24 h of culture compared to control donors (P = 0.007), linked to less cell death (P = 0.08), decreased expression of hypoxia-related genes (Hif1a P = 0.04; IRP94 P = 0.008), and increased intra-cellular (P = 0.04) and nuclear HMGB1. The use of RIPC in recipients only did not allow for reversal of diabetes, with increased serum HMGB1 at day 1; the three other groups demonstrated significantly better outcomes. Performing RIPC in the donors increases islet yield and resistance to hypoxia. Validation is needed, but this strategy could help to decrease the number of donors per islet recipient.
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Affiliation(s)
- Vaihere Delaune
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Stéphanie Lacotte
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Quentin Gex
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Florence Slits
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Arianna Kahler-Quesada
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Andrea Peloso
- Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Lorenzo A Orci
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Thierry Berney
- Cell Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Transplantation Division, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Christian Toso
- Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
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33
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Groot Nibbelink M, Skrzypek K, Karbaat L, Both S, Plass J, Klomphaar B, van Lente J, Henke S, Karperien M, Stamatialis D, van Apeldoorn A. An important step towards a prevascularized islet microencapsulation device: in vivo prevascularization by combination of mesenchymal stem cells on micropatterned membranes. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2018; 29:174. [PMID: 30413974 PMCID: PMC6244873 DOI: 10.1007/s10856-018-6178-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 10/17/2018] [Indexed: 06/08/2023]
Abstract
Extrahepatic transplantation of islets of Langerhans could aid in better survival of islets after transplantation. When islets are transfused into the liver 60-70% of them are lost immediately after transplantation. An important factor for a successful extrahepatic transplantation is a well-vascularized tissue surrounding the implant. There are many strategies known for enhancing vessel formation such as adding cells with endothelial potential, the combination with angiogenic factors and / or applying surface topography at the exposed surface of the device. Previously we developed porous, micropatterned membranes which can be applied as a lid for an islet encapsulation device and we showed that the surface topography induces human umbilical vein endothelial cell (HUVEC) alignment and interconnection. This was achieved without the addition of hydrogels, often used in angiogenesis assays. In this work, we went one step further towards clinical implementation of the device by combining this micropatterned lid with Mesenchymal Stem Cells (MSCs) to facilitate prevascularization in vivo. As for HUVECs, the micropatterned membranes induced MSC alignment and organization in vitro, an important contributor to vessel formation, whereas in vivo (subcutaneous rat model) they contributed to improved implant prevascularization. In fact, the combination of MSCs seeded on the micropatterned membrane induced the highest vessel formation score in 80% of the sections.
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Affiliation(s)
- Milou Groot Nibbelink
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands.
| | - Katarzyna Skrzypek
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Lisanne Karbaat
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Sanne Both
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Jacqueline Plass
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Bettie Klomphaar
- Biomedical Signals and Systems, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Jéré van Lente
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Sieger Henke
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Marcel Karperien
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Dimitrios Stamatialis
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Aart van Apeldoorn
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
- Complex Tissue Regeneration, MERLN Institute for Technology Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
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Stephens CH, Orr KS, Acton AJ, Tersey SA, Mirmira RG, Considine RV, Voytik-Harbin SL. In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo. Am J Physiol Endocrinol Metab 2018; 315:E650-E661. [PMID: 29894201 PMCID: PMC6230705 DOI: 10.1152/ajpendo.00073.2018] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, is needed to advance this cellular therapy. We hypothesized that biophysical properties provided through type I oligomeric collagen macroencapsulation are important considerations when designing strategies to improve islet survival, phenotype, and function. Mouse islets were encapsulated at various Oligomer concentrations (0.5 -3.0 mg/ml) or suspended in media and cultured for 14 days, after which viability, protein expression, and function were assessed. Oligomer-encapsulated islets showed a density-dependent improvement in in vitro viability, cytoarchitecture, and insulin secretion, with 3 mg/ml yielding values comparable to freshly isolated islets. For transplantation into streptozotocin-induced diabetic mice, 500 islets were mixed in Oligomer and injected subcutaneously, where rapid in situ macroencapsulation occurred, or injected with saline. Mice treated with Oligomer-encapsulated islets exhibited rapid (within 24 h) diabetes reversal and maintenance of normoglycemia for 14 (immunocompromised), 90 (syngeneic), and 40 days (allogeneic). Histological analysis showed Oligomer-islet engraftment with maintenance of islet cytoarchitecture, revascularization, and no foreign body response. Oligomer-islet macroencapsulation may provide a useful strategy for prolonging the health and function of cultured islets and has potential as a subcutaneous injectable islet transplantation strategy for treatment of T1D.
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Affiliation(s)
| | - Kara S Orr
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana
| | - Anthony J Acton
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana
| | - Sarah A Tersey
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana
| | - Raghavendra G Mirmira
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana
| | - Robert V Considine
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana
| | - Sherry L Voytik-Harbin
- Weldon School of Biomedical Engineering, Purdue University , West Lafayette, Indiana
- Department of Basic Medical Sciences, Purdue University , West Lafayette, Indiana
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Sigmundsson K, Ojala JR, Öhman MK, Österholm AM, Moreno-Moral A, Domogatskaya A, Chong LY, Sun Y, Chai X, Steele JA, George B, Patarroyo M, Nilsson AS, Rodin S, Ghosh S, Stevens MM, Petretto E, Tryggvason K. Culturing functional pancreatic islets on α5-laminins and curative transplantation to diabetic mice. Matrix Biol 2018; 70:5-19. [DOI: 10.1016/j.matbio.2018.03.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/22/2018] [Accepted: 03/22/2018] [Indexed: 12/15/2022]
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Skrzypek K, Nibbelink MG, Karbaat LP, Karperien M, van Apeldoorn A, Stamatialis D. An important step towards a prevascularized islet macroencapsulation device-effect of micropatterned membranes on development of endothelial cell network. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2018; 29:91. [PMID: 29938334 PMCID: PMC6018599 DOI: 10.1007/s10856-018-6102-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 06/05/2018] [Indexed: 05/23/2023]
Abstract
The development of immune protective islet encapsulation devices could allow for islet transplantation in the absence of immunosuppression. However, the immune protective membrane / barrier introduced there could also impose limitations in transport of oxygen and nutrients to the encapsulated cells resulting to limited islet viability. In the last years, it is well understood that achieving prevascularization of the device in vitro could facilitate its connection to the host vasculature after implantation, and therefore could provide sufficient blood supply and oxygenation to the encapsulated islets. However, the microvascular networks created in vitro need to mimic well the highly organized vasculature of the native tissue. In earlier study, we developed a functional macroencapsulation device consisting of two polyethersulfone/polyvinylpyrrolidone (PES/PVP) membranes, where a bottom microwell membrane provides good separation of encapsulated islets and the top flat membrane acts as a lid. In this work, we investigate the possibility of creating early microvascular networks on the lid of this device by combining novel membrane microfabrication with co-culture of human umbilical vein endothelial cell (HUVEC) and fibroblasts. We create thin porous microstructured PES/PVP membranes with solid and intermittent line-patterns and investigate the effect of cell alignment and cell interconnectivity as a first step towards the development of a stable prevascularized layer in vitro. Our results show that, in contrast to non-patterned membranes where HUVECs form unorganized HUVEC branch-like structures, for the micropatterned membranes, we can achieve cell alignment and the co-culture of HUVECs on a monolayer of fibroblasts attached on the membranes with intermittent line-pattern allows for the creation of HUVEC branch-like structures over the membrane surface. This important step towards creating early microvascular networks was achieved without the addition of hydrogels, often used in angiogenesis assays, as gels could block the pores of the membrane and limit the transport properties of the islet encapsulation device.
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Affiliation(s)
- Katarzyna Skrzypek
- Bioartificial organs, Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
| | - Milou Groot Nibbelink
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
| | - Lisanne P Karbaat
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
| | - Marcel Karperien
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
| | - Aart van Apeldoorn
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
- Complex Tissue Regeneration, MERLN Institute for Technology Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Dimitrios Stamatialis
- Bioartificial organs, Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
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Zhao Y, Liu Y, Yuan J, Dai X, Niu M, Sun X, Kuang D, Wang W, Tong P, Li N, Xiang L, Jia Y, Dai J, Chen H. Regeneration of islet β-cells in tree shrews and rats. Animal Model Exp Med 2018; 1:152-161. [PMID: 30891560 PMCID: PMC6388076 DOI: 10.1002/ame2.12023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 06/11/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUD Current understanding of injury and regeneration of islet β-cells in diabetes is mainly based on rodent studies. The tree shrew is now generally accepted as being among the closest living relatives of primates, and has been widely used in animal experimentation. However, there are few reports on islet cell composition and regeneration of β-cells in tree shrews. METHODS In this study, we examined the changes in islet cell composition and regeneration of β-cells after streptozotocin (STZ) treatment in tree shrews compared with Sprague-Dawley rats. Injury and regeneration of islet β-cells were observed using hematoxylin and eosin (HE) staining and immunohistochemical staining for insulin, glucagon, somatostatin and PDX-1. RESULTS Our data showed that in rats islet injury was most obvious on day 3 after injection, and islet morphologies were significantly restored by day 21. Regeneration of islet β-cells was very pronounced in rats, and mainly involved regeneration of centro-acinar cells and transformation of extra-islet ductal cells. In tree shrews, the regeneration of islet β-cells was not as significant. On days 3 and 7, only scattered regenerated cells were observed in the remaining islets. Further, no regeneration of centro-acinar cells was observed. CONCLUSION The results suggest that the repair mechanism of islet β-cells in tree shrews is similar to that of humans.
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Affiliation(s)
- Yu‐Qiong Zhao
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Ya‐Qian Liu
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Ji‐Fang Yuan
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Xin Dai
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Miao‐Miao Niu
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Xiao‐Mei Sun
- The Institute of Medical BiologyThe Chinese Academy of Medical Science and Peking Union Medical CollegeKunmingChina
- Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious DiseasesCenter of Tree Shrew Germplasm ResourcesKunmingChina
| | - De‐Xuan Kuang
- The Institute of Medical BiologyThe Chinese Academy of Medical Science and Peking Union Medical CollegeKunmingChina
- Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious DiseasesCenter of Tree Shrew Germplasm ResourcesKunmingChina
| | - Wen‐Guang Wang
- The Institute of Medical BiologyThe Chinese Academy of Medical Science and Peking Union Medical CollegeKunmingChina
- Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious DiseasesCenter of Tree Shrew Germplasm ResourcesKunmingChina
| | - Pin‐Fen Tong
- The Institute of Medical BiologyThe Chinese Academy of Medical Science and Peking Union Medical CollegeKunmingChina
- Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious DiseasesCenter of Tree Shrew Germplasm ResourcesKunmingChina
| | - Na Li
- The Institute of Medical BiologyThe Chinese Academy of Medical Science and Peking Union Medical CollegeKunmingChina
- Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious DiseasesCenter of Tree Shrew Germplasm ResourcesKunmingChina
| | - Lei Xiang
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Yun‐Xiao Jia
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
| | - Jie‐Jie Dai
- The Institute of Medical BiologyThe Chinese Academy of Medical Science and Peking Union Medical CollegeKunmingChina
- Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious DiseasesCenter of Tree Shrew Germplasm ResourcesKunmingChina
| | - Hua Chen
- Chinese PLA General HospitalLaboratory Animal CenterBeijingChina
- State Key Laboratory of Kidney DiseasesChinese PLA General HospitalBeijingChina
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van Megen KM, van ’t Wout EJT, Forman SJ, Roep BO. A Future for Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes. Front Immunol 2018; 9:690. [PMID: 29696017 PMCID: PMC5904498 DOI: 10.3389/fimmu.2018.00690] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 03/20/2018] [Indexed: 12/29/2022] Open
Affiliation(s)
- Kayleigh M. van Megen
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute at the City of Hope, Duarte, CA, United States
| | - Ernst-Jan T. van ’t Wout
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute at the City of Hope, Duarte, CA, United States
| | - Stephen J. Forman
- Department of Hematology & Hematopoietic Cell Transplantation, T Cell Therapeutics Research Laboratory, City of Hope Beckman Research Institute and Medical Center, Duarte, CA, United States
| | - Bart O. Roep
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute at the City of Hope, Duarte, CA, United States
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
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Simeonovic CJ, Popp SK, Starrs LM, Brown DJ, Ziolkowski AF, Ludwig B, Bornstein SR, Wilson JD, Pugliese A, Kay TWH, Thomas HE, Loudovaris T, Choong FJ, Freeman C, Parish CR. Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. PLoS One 2018; 13:e0191360. [PMID: 29415062 PMCID: PMC5802856 DOI: 10.1371/journal.pone.0191360] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 01/03/2018] [Indexed: 12/20/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.
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Affiliation(s)
- Charmaine J. Simeonovic
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
- * E-mail:
| | - Sarah K. Popp
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Lora M. Starrs
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Debra J. Brown
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Andrew F. Ziolkowski
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Barbara Ludwig
- Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany
| | - Stefan R. Bornstein
- Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany
| | - J. Dennis Wilson
- Department of Endocrinology, The Canberra Hospital, Woden, Australian Capital Territory, Australia
| | - Alberto Pugliese
- Diabetes Research Institute, Departments of Medicine, Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Thomas W. H. Kay
- St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Victoria, Australia
| | - Helen E. Thomas
- St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Victoria, Australia
| | - Thomas Loudovaris
- St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Victoria, Australia
| | - Fui Jiun Choong
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Craig Freeman
- Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Christopher R. Parish
- Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
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Barra JM, Tse HM. Redox-Dependent Inflammation in Islet Transplantation Rejection. Front Endocrinol (Lausanne) 2018; 9:175. [PMID: 29740396 PMCID: PMC5924790 DOI: 10.3389/fendo.2018.00175] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/03/2018] [Indexed: 12/19/2022] Open
Abstract
Type 1 diabetes is an autoimmune disease that results in the progressive destruction of insulin-producing pancreatic β-cells inside the islets of Langerhans. The loss of this vital population leaves patients with a lifelong dependency on exogenous insulin and puts them at risk for life-threatening complications. One method being investigated to help restore insulin independence in these patients is islet cell transplantation. However, challenges associated with transplant rejection and islet viability have prevented long-term β-cell function. Redox signaling and the production of reactive oxygen species (ROS) by recipient immune cells and transplanted islets themselves are key players in graft rejection. Therefore, dissipation of ROS generation is a viable intervention that can protect transplanted islets from immune-mediated destruction. Here, we will discuss the newly appreciated role of redox signaling and ROS synthesis during graft rejection as well as new strategies being tested for their efficacy in redox modulation during islet cell transplantation.
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Pathak S, Regmi S, Gupta B, Poudel BK, Pham TT, Yong CS, Kim JO, Kim JR, Park MH, Bae YK, Yook S, Ahn CH, Jeong JH. Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice. Drug Deliv 2017; 24:1350-1359. [PMID: 28911248 PMCID: PMC8241191 DOI: 10.1080/10717544.2017.1377317] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 09/02/2017] [Accepted: 09/05/2017] [Indexed: 12/18/2022] Open
Abstract
Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506M group. The single injection of FK506M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.
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Affiliation(s)
- Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Biki Gupta
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Bijay K. Poudel
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Tung Thanh Pham
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Jae-Ryong Kim
- Department of Biochemistry and Molecular Biology and Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Min Hui Park
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Young Kyung Bae
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu, Republic of Korea
| | - Cheol-Hee Ahn
- Engineering Research Institute, Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
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Qin J, Arakawa Y, Morita M, Fung JJ, Qian S, Lu L. C-C Chemokine Receptor Type 2-Dependent Migration of Myeloid-Derived Suppressor Cells in Protection of Islet Transplants. Transplantation 2017; 101:1793-1800. [PMID: 27755503 PMCID: PMC5393972 DOI: 10.1097/tp.0000000000001529] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Islet transplantation is a promising therapeutic approach to restore the physical response to blood glucose in type 1 diabetes. Current chronic use of immunosuppressive reagents for preventing islet allograft rejection is associated with severe complications. In addition, many of the immunosuppressive drugs are diabetogenic. The induction of transplant tolerance to eliminate the dependency on immunosuppression is ideal, but remains challenging. METHODS Addition of hepatic stellate cells allowed generation of myeloid-derived suppressor cells (MDSC) from precursors in mouse bone marrow. Migration of MDSC was examined in an islet allograft transplant model by tracking the systemic administered MDSC from CD45.1 congenic mice. RESULTS The generated MDSC were expressed C-C chemokine receptor type 2 (CCR2), which was enhanced by exposure to interferon-γ. A single systemic administration of MDSC markedly prolonged survival of islet allografts without requirement of immunosuppression. Tracking the administered MDSC showed that they promptly migrated to the islet graft sites, at which point they exerted potent immune suppressive activity by inhibiting CD8 T cells, enhancing regulatory T cell activity. MDSC generated from CCR2 mice failed to be mobilized and lost tolerogenic activity in vivo, but sustained suppressive activity in vitro. CONCLUSIONS MDSC migration was dependent on expression of CCR2, whereas CCR2 does not directly participate in immune suppression. Expression of CCR2 needs to be closely monitored for quality control purpose when MDSC are generated in vitro for immune therapy.
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Affiliation(s)
- Jie Qin
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Yusuke Arakawa
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Miwa Morita
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - John J Fung
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Shiguang Qian
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
| | - Lina Lu
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
- Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH
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Smink AM, Li S, Swart DH, Hertsig DT, de Haan BJ, Kamps JAAM, Schwab L, van Apeldoorn AA, de Koning E, Faas MM, Lakey JRT, de Vos P. Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet-transplantation enhances immediate post-transplant islet graft function but not long-term normoglycemia. J Biomed Mater Res A 2017; 105:2533-2542. [PMID: 28470672 PMCID: PMC5575460 DOI: 10.1002/jbm.a.36101] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/20/2017] [Accepted: 04/26/2017] [Indexed: 12/22/2022]
Abstract
The liver as transplantation site for pancreatic islets is associated with significant loss of islets, which can be prevented by grafting in a prevascularized, subcutaneous scaffold. Supporting vascularization of a scaffold to limit the period of ischemia is challenging and was developed here by applying liposomes for controlled release of angiogenic factors. The angiogenic capacity of platelet-derived growth factor, vascular endothelial growth factor, acidic fibroblast growth factor (aFGF), and basic FGF were compared in a tube formation assay. Furthermore, the release kinetics of different liposome compositions were tested. aFGF and L-α-phosphatidylcholine/cholesterol liposomes were selected to support vascularization. Two dosages of aFGF-liposomes (0.5 and 1.0 μg aFGF per injection) were administered weekly for a month after which islets were transplanted. We observed enhanced efficacy in the immediate post-transplant period compared to the untreated scaffolds. However, on the long-term, glucose levels of the aFGF treated animals started to increase to diabetic levels. These results suggest that injections with aFGF liposomes do improve vascularization and the immediate restoration of blood glucose levels but does not facilitate the long-term survival of islets. Our data emphasize the need for long-term studies to evaluate potential beneficial and adverse effects of vascularization protocols of scaffolds. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2533-2542, 2017.
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Affiliation(s)
- Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Shiri Li
- Department of Surgery, University of California Irvine, Orange
| | - Daniël H Swart
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Bart J de Haan
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan A A M Kamps
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Aart A van Apeldoorn
- Department of Developmental BioEngineering, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Eelco de Koning
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marijke M Faas
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jonathan R T Lakey
- Department of Surgery, University of California Irvine, Orange.,Department of Biomedical Engineering, University of California Irvine, Irvine
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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The Efficacy of a Prevascularized, Retrievable Poly(D,L,-lactide-co-ε-caprolactone) Subcutaneous Scaffold as Transplantation Site for Pancreatic Islets. Transplantation 2017; 101:e112-e119. [PMID: 28207637 DOI: 10.1097/tp.0000000000001663] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The liver as transplantation site for human pancreatic islets is a harsh microenvironment for islets and it lacks the ability to retrieve the graft. A retrievable, extrahepatic transplantation site that mimics the pancreatic environment is desired. Ideally, this transplantation site should be located subdermal for easy surgical-access but this never resulted in normoglycemia. Here, we describe the design and efficacy of a novel prevascularized, subcutaneously implanted, retrievable poly (D,L-lactide-co-ε-caprolactone) scaffold. METHOD Three dosages of rat islets, that is, 400, 800, and 1200, were implanted in immune compromised mice to test the efficacy (n = 5). Islet transplantation under the kidney capsule served as control (n = 5). The efficacy was determined by nonfasting blood glucose measurements and glucose tolerance tests. RESULTS Transplantation of 800 (n = 5) and 1200 islets (n = 5) into the scaffold reversed diabetes in respectively 80 and 100% of the mice within 6.8 to 18.5 days posttransplant. The marginal dose of 400 islets (n = 5) induced normoglycemia in 20%. The glucose tolerance test showed major improvement of the glucose clearance in the scaffold groups compared to diabetic controls. However, the kidney capsule was slightly more efficacious because all 800 (n = 5) and 1200 islets (n = 5) recipients and 40% of the 400 islets (n = 5) recipients became normoglycemic within 8 days. Removal of the scaffolds or kidney grafts resulted in immediate return to hyperglycemia. Normoglycemia was not achieved with 1200 islets in the unmodified skin group. CONCLUSIONS Our findings demonstrate that the prevascularized poly (D,L-lactide-co-ε-caprolactone) scaffold maintains viability and function of islets in the subcutaneous site.
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Delaune V, Berney T, Lacotte S, Toso C. Intraportal islet transplantation: the impact of the liver microenvironment. Transpl Int 2017; 30:227-238. [DOI: 10.1111/tri.12919] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 11/09/2016] [Accepted: 01/16/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Vaihere Delaune
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
| | - Thierry Berney
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
- Cell Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - Stéphanie Lacotte
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - Christian Toso
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
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Pouliquen E, Baltzinger P, Lemle A, Chen CC, Parissiadis A, Borot S, Frimat L, Girerd S, Berney T, Lablanche S, Benhamou PY, Morelon E, Badet L, Dubois V, Kessler L, Thaunat O. Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function. Am J Transplant 2017; 17:462-473. [PMID: 27343461 DOI: 10.1111/ajt.13936] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 05/24/2016] [Accepted: 06/22/2016] [Indexed: 01/25/2023]
Abstract
Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.
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Affiliation(s)
- E Pouliquen
- Hospices Civils de Lyon, Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.,INSERM U1111, Université de Lyon, Lyon, France
| | - P Baltzinger
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle MIRNED, EA 7293 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - A Lemle
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle MIRNED, EA 7293 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - C-C Chen
- INSERM U1111, Université de Lyon, Lyon, France
| | - A Parissiadis
- Laboratoire d' histocompatibilité, Etablissement Français de Sang, Strasbourg, France
| | - S Borot
- Centre Hospitalier Universitaire Jean Minjoz, Service d'Endocrinologie-Métabolisme et Diabétologie-Nutrition, Besançon, France
| | - L Frimat
- Centre Hospitalier Universitaire de Nancy, Service de Néphrologie, Nancy, France
| | - S Girerd
- Centre Hospitalier Universitaire de Nancy, Service de Néphrologie, Nancy, France
| | - T Berney
- Departement of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - S Lablanche
- Departement of Surgery, Islet Isolation, and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - P Y Benhamou
- Département d'Endocrinologie, Pôle DigiDune, Hôpital Universitaire de Grenoble, Université Grenoble Alpes, Grenoble, France
| | - E Morelon
- Hospices Civils de Lyon, Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.,INSERM U1111, Université de Lyon, Lyon, France
| | - L Badet
- Hospices Civils de Lyon, Service d'Urologie et de Chirurgie de la Transplantation, Pôle Chirurgie, Hôpital Edouard Herriot, Lyon, France
| | - V Dubois
- Laboratoire d'Histocompatibilité, Etablissement Français du Sang, Lyon, France
| | - L Kessler
- Hôpitaux Universitaires de Strasbourg, Service d'Endocrinologie Diabète et Maladies Métaboliques, Pôle MIRNED, EA 7293 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - O Thaunat
- Hospices Civils de Lyon, Service de Transplantation, Néphrologie et Immunologie Clinique, Hôpital Edouard Herriot, Lyon, France.,INSERM U1111, Université de Lyon, Lyon, France
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Adin CA, Vangundy ZC, Papenfuss TL, Xu F, Ghanem M, Lakey J, Hadley GA. Physiologic Doses of Bilirubin Contribute to Tolerance of Islet Transplants by Suppressing the Innate Immune Response. Cell Transplant 2017; 26:11-21. [PMID: 27393133 PMCID: PMC5657680 DOI: 10.3727/096368916x692096] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 07/07/2016] [Accepted: 09/23/2016] [Indexed: 01/02/2023] Open
Abstract
Bilirubin has been recognized as a powerful cytoprotectant when used at physiologic doses and was recently shown to have immunomodulatory effects in islet allograft transplantation, conveying donor-specific tolerance in a murine model. We hypothesized that bilirubin, an antioxidant, acts to suppress the innate immune response to islet allografts through two mechanisms: 1) by suppressing graft release of damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and 2) by producing a tolerogenic phenotype in antigen-presenting cells. Bilirubin was administered intraperitoneally before pancreatic procurement or was added to culture media after islet isolation in AJ mice. Islets were exposed to transplant-associated nutrient deprivation and hypoxia. Bilirubin significantly decreased islet cell death after isolation and hypoxic stress. Bilirubin supplementation of islet media also decreased the release of DAMPs (HMGB1), inflammatory cytokines (IL-1β and IL-6), and chemokines (MCP-1). Cytoprotection was mediated by the antioxidant effects of bilirubin. Treatment of macrophages with bilirubin induced a regulatory phenotype, with increased expression of PD-L1. Coculture of these macrophages with splenocytes led to expansion of Foxp3+ Tregs. In conclusion, exogenous bilirubin supplementation showed cytoprotective and antioxidant effects in a relevant model of islet isolation and hypoxic stress. Suppression of DAMP release, alterations in cytokine profiles, and tolerogenic effects on macrophages suggest that the use of this natural antioxidant may provide a method of preconditioning to improve outcomes after allograft transplantation.
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Affiliation(s)
- Christopher A. Adin
- Department of Veterinary Clinical Sciences, North Carolina State University, Raleigh, NC, USA
| | - Zachary C. Vangundy
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Tracey L. Papenfuss
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Feng Xu
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Mostafa Ghanem
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Jonathan Lakey
- Department of Surgery, University of California, Irvine, Irvine, CA, USA
| | - Gregg A. Hadley
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA
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Pathak S, Regmi S, Gupta B, Poudel BK, Pham TT, Kim JR, Park PH, Yong CS, Kim JO, Bae YK, Kim SK, Jeong JH. Hybrid Congregation of Islet Single Cells and Curcumin-Loaded Polymeric Microspheres as an Interventional Strategy to Overcome Apoptosis Associated with Pancreatic Islets Transplantation. ACS APPLIED MATERIALS & INTERFACES 2016; 8:25702-25713. [PMID: 27666317 DOI: 10.1021/acsami.6b07897] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Hypoxic or near-anoxic conditions that occur in the core of transplanted islets induce necrosis and apoptosis during the early stages after transplantation, primarily due to loss of vascularization during the isolation process. Moreover, secretion of various cytokines from pancreatic islets is detrimental to the viability of islet cells in vitro. In this study, we aimed to protect pancreatic islet cells against apoptosis by establishing a method for in situ delivery of curcumin to the pancreatic islets. Self-assembled heterospheroids composed of pancreatic islet cells and curcumin-loaded polymeric microspheres were prepared by the three-dimensional cell culture technique. Release of curcumin in the microenvironment of pancreatic islets promoted survival of the islets. In hypoxic culture conditions, which mimic the in vivo conditions after transplantation, viability of the islets was significantly improved, as indicated by a decreased expression of pro-apoptotic protein and an increased expression of anti-apoptotic protein. Additionally, oxidative stress-induced cell death was suppressed. Thus, unlike co-transplantation of pancreatic islets and free microspheres, which provided a wide distribution of microspheres throughout the transplanted area, the heterospheroid transplantation resulted in colocalization of pancreatic islet cells and microspheres, thereby exerting beneficial effects on the cells.
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Affiliation(s)
- Shiva Pathak
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Shobha Regmi
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Biki Gupta
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Bijay K Poudel
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Tung Thanh Pham
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jae-Ryong Kim
- Department of Biochemistry and Molecular Biology and Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University , Daegu 42415, Republic of Korea
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Young Kyung Bae
- Department of Pathology, Yeungnam University College of Medicine , Daegu 42415, Republic of Korea
| | - Sang Kyoon Kim
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF) , Daegu 41061, Republic of Korea
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University , Gyeongsan, Gyeongbuk 38541, Republic of Korea
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Liu S, Zhang L, Cheng J, Lu Y, Liu J. Sustained release of hepatocyte growth factor by cationic self-assembling peptide/heparin hybrid hydrogel improves β-cell survival and function through modulating inflammatory response. Int J Nanomedicine 2016; 11:4875-4890. [PMID: 27729786 PMCID: PMC5042198 DOI: 10.2147/ijn.s108921] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Inflammatory response is a major cause of grafts dysfunction in islet transplantation. Hepatocyte growth factor (HGF) had shown anti-inflammatory activity in multiple diseases. In this study, we aim to deliver HGF by self-assembling peptide/heparin (SAP/Hep) hybrid gel to protect β-cell from inflammatory injury. The morphological and slow release properties of SAPs were analyzed. Rat INS-1 β-cell line was treated with tumor necrosis factor α in vitro and transplanted into rat kidney capsule in vivo, and the viability, apoptosis, function, and inflammation of β-cells were evaluated. Cationic KLD1R and KLD2R self-assembled to nanofiber hydrogel, which showed higher binding affinity for Hep and HGF because of electrostatic interaction. Slow release of HGF from cationic SAP/Hep gel is a two-step mechanism involving binding affinity with Hep and molecular diffusion. In vitro and in vivo results showed that HGF-loaded KLD2R/Hep gel promoted β-cell survival and insulin secretion, and inhibited cell apoptosis, cytokine release, T-cell infiltration, and activation of NFκB/p38 MAPK pathways in β-cells. This study suggested that SAP/Hep gel is a promising carrier for local delivery of bioactive proteins in islet transplantation.
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Affiliation(s)
- Shuyun Liu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital
| | - Lanlan Zhang
- Institute for Nanobiomedical Technology and Membrane Biology, Sichuan University, Chengdu, People's Republic of China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital
| | - Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital
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Karakose M, Pinarli FA, Arslan MS, Boyuk G, Boztok B, Albayrak A, Ulus AT, Cakal E, Delibasi T. Comparison of the Ovary and Kidney as Sites for Islet Transplantation in Diabetic Rats. Transplant Proc 2016; 48:2216-20. [PMID: 27569973 DOI: 10.1016/j.transproceed.2016.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/30/2016] [Accepted: 04/25/2016] [Indexed: 11/29/2022]
Abstract
BACKGROUND Currently, the most commonly used site for clinical islet transplantation is the liver although it is far from being an ideal site. Low oxygen tension and the induction of an inflammatory response impair islet implantation and lead to significant early loss of islet. The present study aimed to investigate and compare the efficacy of islet transplantation to the ovary and kidney subcapsule in diabetic rats. METHODS The study was performed with 3 groups of rats (control, ovary, and kidney subcapsule) including 6 Sprague female rats each. Diabetes model was created with the use of streptozotocin, and blood glucose levels of the rats were measured after 72 hours. Thirty days after the transplantation, blood samples were obtained from the rats, and then pancreas, kidney, and ovary specimens were fixed in 10% formaldehyde and the experiment completed. After staining with hematoxylin and eosin, the tissue samples were morphologically evaluated by a specialist histopathologist. RESULTS Changes in mean blood glucose and C-peptide levels were statistically significant in the ovary and kidney subcapsule groups. Histologic examination revealed that granulosus insulin-bearing cells were detected in the islet grafts of both ovary and kidney subcapsule groups. The renal subcapsule group had inflammation signs on histologic examination. The islet cells of both ovary and renal subcapsule groups had no vacuolization. CONCLUSIONS We showed that the ovary might be a new site for islet transplantation. Further research should be done on whether the initial results of this study can be reproduced in larger numbers of animal models and eventually in humans.
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Affiliation(s)
- M Karakose
- Department of Endocrinology and Metabolism, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey.
| | - F A Pinarli
- Department of Genetic and Medical Research Center, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - M S Arslan
- Department of Endocrinology and Metabolism, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - G Boyuk
- Adacell Laboratory, Pancreas Islet Cell Research Center, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - B Boztok
- Adacell Laboratory, Pancreas Islet Cell Research Center, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - A Albayrak
- Department of Pathology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - A T Ulus
- Department of Cardiovascular Surgery, Hacettepe University School of Medicine, Ankara, Turkey
| | - E Cakal
- Department of Endocrinology and Metabolism, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - T Delibasi
- Department of Internal Medicine, Kastamonu University School of Medicine, Kastamonu, Turkey
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