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Liu M, Deng H, Liu C, Wang L, Liao Z, Li D, Chen Y, Li J, Dong J, Sun X, Wang C, Huang L, Dong L, Xiao J. Islet transplantation in immunomodulatory nanoparticle-remodeled spleens. Sci Transl Med 2025; 17:eadj9615. [PMID: 40397715 DOI: 10.1126/scitranslmed.adj9615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/08/2024] [Accepted: 04/29/2025] [Indexed: 05/23/2025]
Abstract
Islet transplantation is a promising therapy for insulin-dependent diabetes. However, immune rejection and insufficient vascularization hinder the survival and function of transplanted islets. Here, we show effective engraftment of vascularized and functional mouse and rat islets transplanted into biomaterial-remodeled spleens of nonimmunosuppressed rodents and human islets transplanted into the remodeled spleens of nonhuman primates (NHPs) on varying degrees of immunosuppression. We found evidence that konjac glucomannan-modified silica nanoparticles (KSiNPs) remodeled the spleen into an extracellular matrix (ECM)-rich, immunosuppressive niche to support the survival of syngeneic or xenogeneic islets. Transplanted islets in the remodeled spleens showed improved engraftment, neovascularization, and functionality and restored normoglycemia in streptozotocin (STZ)-induced type 1 diabetic models in the mice and macaques, with stable insulin and C-peptide secretion in mice for 90 days and macaques for 28 days. KSiNP injection and islet transplantation into macaque spleens under B-ultrasound guidance were preclinically feasible. These findings highlight the safety and effectiveness of spleen tissue remodeling in supporting the survival and function of transplanted islets, providing a promising strategy for treating type 1 diabetes mellitus (T1DM).
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Affiliation(s)
- Mi Liu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Department of Wound Healing of the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, 999078, Macau SAR, China
- Affiliated Cixi Hospital, Wenzhou Medical University, Cixi, 315300, China
| | - Huiming Deng
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Department of Wound Healing of the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China
| | - Chunyan Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Lintao Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Zhongkai Liao
- Department of Organ Transplantation, Second Affiliated Hospital of Hainan Medical University, Haikou, 570216, China
| | - Desheng Li
- Department of Organ Transplantation, Second Affiliated Hospital of Hainan Medical University, Haikou, 570216, China
| | - Yan Chen
- Department of Oncology of the First Affiliated Hospital and Cancer Institute, Hainan Medical University, Haikou, 570102, China
| | - Jianhui Li
- Division of Hepatobiliary Pancreatic Surgery, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jianhui Dong
- Institute of Transplantation Medicine, Second Affiliated Hospital of Guangxi Medical University; Guangxi Clinical Research Center for Organ Transplantation; Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning 530007, China
| | - Xuyong Sun
- Institute of Transplantation Medicine, Second Affiliated Hospital of Guangxi Medical University; Guangxi Clinical Research Center for Organ Transplantation; Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning 530007, China
| | - Chunming Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, 999078, Macau SAR, China
| | - Ling Huang
- School of Hainan Provincial Drug Safety Evaluation Research Center, Hainan Medical University, Haikou, 571199, China
- Center for Pharmacovigilance of Hainan Province, Hainan Medical Products Administration, Haikou, 570216, China
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China
| | - Jian Xiao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Department of Wound Healing of the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China
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2
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Aplin AC, Aghazadeh Y, Mohn OG, Hull-Meichle RL. Role of the Pancreatic Islet Microvasculature in Health and Disease. J Histochem Cytochem 2024; 72:711-728. [PMID: 39601198 PMCID: PMC11600425 DOI: 10.1369/00221554241299862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
The pancreatic islet vasculature comprises microvascular endothelial cells surrounded by mural cells (pericytes). Both cell types support the islet by providing (1) a conduit for delivery and exchange of nutrients and hormones; (2) paracrine signals and extracellular matrix (ECM) components that support islet development, architecture, and endocrine function; and (3) a barrier against inflammation and immune cell infiltration. In type 2 diabetes, the islet vasculature becomes inflamed, showing loss of endothelial cells, detachment, and/or trans-differentiation of pericytes, vessel dilation, and excessive ECM deposition. While most work to date has focused either on endothelial cells or pericytes in isolation, it is very likely that the interaction between these cell types and disruption of that interaction in diabetes are critically important. In fact, dissociation of pericytes from endothelial cells is an early, key feature of microvascular disease in multiple tissues/disease states. Moreover, in beta-cell replacement therapy, co-transplantation with microvessels versus endothelial cells alone is substantially more effective in improving survival and function of the transplanted cells. Ongoing studies, including characterization of islet vascular cell signatures, will aid in the identification of new therapeutic targets aimed at improving islet function and benefiting people living with all forms of diabetes.
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Affiliation(s)
- Alfred C. Aplin
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Yasaman Aghazadeh
- Institut de Recherches Cliniques de Montreal (IRCM), Department of Medicine, University of Montreal, and Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Olivia G. Mohn
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
| | - Rebecca L. Hull-Meichle
- Seattle Institute for Biomedical and Clinical Research, and Research Service, Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington; and Alberta Diabetes Institute and Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada
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3
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Langlois A, Pinget M, Kessler L, Bouzakri K. Islet Transplantation: Current Limitations and Challenges for Successful Outcomes. Cells 2024; 13:1783. [PMID: 39513890 PMCID: PMC11544954 DOI: 10.3390/cells13211783] [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: 09/26/2024] [Revised: 10/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Islet transplantation is a promising approach for treating patients with unstable T1DM. However, it is confronted with numerous obstacles throughout the various stages of the transplantation procedure. Significant progress has been made over the last 25 years in understanding the mechanisms behind the loss of functional islet mass and in developing protective strategies. Nevertheless, at present, two to three pancreases are still needed to treat a single patient, which limits the maximal number of patients who can benefit from islet transplantation. Thus, this publication provides an overview of recent scientific findings on the various issues affecting islet transplantation. Specifically, we will focus on the understanding of the mechanisms involved and the strategies developed to alleviate these problems from the isolation stage to the post-transplantation phase. Finally, we hope that this review will highlight new avenues of action, enabling us to propose pancreatic islet transplantation to a maximum number of patients with T1DM.
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Affiliation(s)
- Allan Langlois
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| | - Michel Pinget
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| | - Laurence Kessler
- Department of Endocrinology, Diabetes and Nutrition, University Hospital of Strasbourg, 67200 Strasbourg, France;
- Inserm UMR 1260, Nanomédicine Regenerative, University of Strasbourg, 67085 Strasbourg, France
| | - Karim Bouzakri
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
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Wang L, Wan J, Xu Y, Huang Y, Wang D, Zhu D, Chen Q, Lu Y, Guo Q. Endothelial Cells Promote Pseudo-islet Function Through BTC-EGFR-JAK/STAT Signaling Pathways. Ann Biomed Eng 2024; 52:2610-2626. [PMID: 38829457 DOI: 10.1007/s10439-024-03548-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 05/20/2024] [Indexed: 06/05/2024]
Abstract
Interactions between cells are of fundamental importance in affecting cell function. In vivo, endothelial cells and islet cells are close to each other, which makes endothelial cells essential for islet cell development and maintenance of islet cell function. We used endothelial cells to construct 3D pseudo-islets, which demonstrated better glucose regulation and greater insulin secretion compared to conventional pseudo-islets in both in vivo and in vitro trials. However, the underlying mechanism of how endothelial cells promote beta cell function localized within islets is still unknown. We performed transcriptomic sequencing, differential gene analysis, and enrichment analysis on two types of pseudo-islets to show that endothelial cells can promote the function of internal beta cells in pseudo-islets through the BTC-EGFR-JAK/STAT signaling pathway. Min6 cells secreted additional BTC after co-culture of endothelial cells with MIN6 cells outside the body. After BTC knockout in vitro, we found that beta cells functioned differently: insulin secretion levels decreased significantly, while the expression of key proteins in the EGFR-mediated JAK/STAT signaling pathway simultaneously decreased, further confirming our results. Through our experiments, we elucidate the molecular mechanisms by which endothelial cells maintain islet function in vitro, which provides a theoretical basis for the construction of pseudo-islets and islet cell transplants for the treatment of diabetes mellitus.
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Affiliation(s)
- Lin Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Jian Wan
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Yang Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Yan Huang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Dongzhi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Donghui Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Qiyang Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Yuhua Lu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Qingsong Guo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
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5
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Félix-Martínez GJ, Osorio-Londoño D, Godínez-Fernández JR. Impact of oxygen and glucose availability on the viability and connectivity of islet cells: A computational study of reconstructed avascular human islets. PLoS Comput Biol 2024; 20:e1012357. [PMID: 39137218 PMCID: PMC11343470 DOI: 10.1371/journal.pcbi.1012357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/23/2024] [Accepted: 07/22/2024] [Indexed: 08/15/2024] Open
Abstract
The experimental study and transplantation of pancreatic islets requires their isolation from the surrounding tissue, and therefore, from the vasculature. Under these conditions, avascular islets rely on the diffusion of peripheral oxygen and nutrients to comply with the requirements of islet cells while responding to changes in body glucose. As a complement to the experimental work, computational models have been widely used to estimate how avascular islets would be affected by the hypoxic conditions found both in culture and transplant sites. However, previous models have been based on simplified representations of pancreatic islets which has limited the reach of the simulations performed. Aiming to contribute with a more realistic model of avascular human islets, in this work we used architectures of human islets reconstructed from experimental data to simulate the availability of oxygen for α, β and δ-cells, emulating culture and transplant conditions at different glucose concentrations. The modeling approach proposed allowed us to quantitatively estimate how the loss of cells due to severe hypoxia would impact interactions between islet cells, ultimately segregating the islet into disconnected subnetworks. According to the simulations performed, islet encapsulation, by reducing the oxygen available within the islets, could severely compromise cell viability. Moreover, our model suggests that even without encapsulation, only microislets composed of less than 100 cells would remain viable in oxygenation conditions found in transplant sites. Overall, in this article we delineate a novel modeling methodology to simulate detailed avascular islets in experimental and transplant conditions with potential applications in the field of islet encapsulation.
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Affiliation(s)
- Gerardo J. Félix-Martínez
- Investigadoras e investigadores por México, Consejo Nacional de Humanidades, Ciencias y Tecnologías, México City, México
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Iztapalapa, México City, México
| | - Diana Osorio-Londoño
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Iztapalapa, México City, México
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Thorngren J, Brboric A, Vasylovska S, Hjelmqvist D, Westermark GT, Saarimäki-Vire J, Kvist J, Balboa D, Otonkoski T, Carlsson PO, Lau J. Efficient Vascular and Neural Engraftment of Stem Cell-Derived Islets. Diabetes 2024; 73:1127-1139. [PMID: 38603470 PMCID: PMC11189832 DOI: 10.2337/db23-0123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/01/2024] [Indexed: 04/13/2024]
Abstract
Pluripotent stem cell-derived islets (SC-islets) have emerged as a new source for β-cell replacement therapy. The function of human islet transplants is hampered by excessive cell death posttransplantation; contributing factors include inflammatory reactions, insufficient revascularization, and islet amyloid formation. However, there is a gap in knowledge of the engraftment process of SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at 3 months posttransplantation and observed that cell apoptosis rates were lower but vascular density was similar in SC-islets compared with human islets. Whereas the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. Oxygenation in the SC-islet grafts was twice as high as that in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, reinnervation of the SC-islets was four- to fivefold higher than that of the human islets. Both SC-islets and human islets contained amyloid at 1 and 3 months posttransplantation. We conclude that the vascular and neural engraftment of SC-islets are superior to those of human islets, but grafts of both origins develop amyloid, with potential long-term consequences. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Julia Thorngren
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Anja Brboric
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Daisy Hjelmqvist
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Jonna Saarimäki-Vire
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jouni Kvist
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Diego Balboa
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Timo Otonkoski
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Joey Lau
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
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Qi B, Ding Y, Zhang Y, Kou L, Zhao YZ, Yao Q. Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes. Biomater Sci 2024; 12:821-836. [PMID: 38168805 DOI: 10.1039/d3bm01295f] [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: 01/05/2024]
Abstract
Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.
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Affiliation(s)
- Boyang Qi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Yang Ding
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Ying Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Longfa Kou
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Qing Yao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China
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French A, Hollister-Lock J, Sullivan BA, Stas E, Hwa AJ, Weir GC, Bonner-Weir S. Enhancement of Subcutaneous Islet Transplant Performance by Collagen 1 Gel. Cell Transplant 2024; 33:9636897241283728. [PMID: 39361612 PMCID: PMC11457190 DOI: 10.1177/09636897241283728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/14/2024] [Accepted: 08/14/2024] [Indexed: 10/05/2024] Open
Abstract
Human islets can be transplanted into the portal vein for T1 diabetes, and a similar procedure is being used in a clinical trial for stem cell-derived beta-like cells. Efforts have been underway to find an alternative transplant site that will foster better islet cell survival and function. Although conceptually attractive, the subcutaneous (SC) site has yielded disappointing results, in spite of some improvements resulting from more attention paid to vascularization and differentiation factors, including collagen. We developed a method to transplant rat islets in a disk of type 1 collagen gel and found improved efficacy of these transplants. Survival of islets following transplantation (tx) was determined by comparing insulin content of the graft to that of the pre-transplant islets from the same isolation. At 14 days after transplantation, grafts of the disks had more than double the recovered insulin than islets transplanted in ungelled collagen. SC grafts of disks had similar insulin content to grafts in a kidney site and in epididymal fat pads. In vivo disks underwent contraction to 10% of initial volume within 24 h but the islets remained healthy and well distributed. Whole mount imaging showed that residual donor vascular cells within the islets expanded and connected to ingrowing host blood vessels. Islets (400 rat islet equivalents (IEQ)) in the collagen disks transplanted into an SC site of NOD scid IL2R gammanull (NSG) mice reversed streptozotocin (STZ)-induced diabetes within 10 days as effectively as transplants in the kidney site. Thus, a simple change of placing islets into a gel of collagen 1 prior to transplantation allowed a prompt reversal of STZ-induced diabetes using SC site.
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Affiliation(s)
- Anna French
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Jennifer Hollister-Lock
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Brooke A. Sullivan
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Eline Stas
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Albert J. Hwa
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Gordon C. Weir
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Susan Bonner-Weir
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
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9
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Chetboun M, Masset C, Maanaoui M, Defrance F, Gmyr V, Raverdy V, Hubert T, Bonner C, Supiot L, Kerleau C, Blancho G, Branchereau J, Karam G, Chelghaf I, Houzet A, Giral M, Garandeau C, Dantal J, Le Mapihan K, Jannin A, Hazzan M, Caiazzo R, Kerr-Conte J, Vantyghem MC, Cantarovich D, Pattou F. Primary Graft Function and 5 Year Insulin Independence After Pancreas and Islet Transplantation for Type 1 Diabetes: A Retrospective Parallel Cohort Study. Transpl Int 2023; 36:11950. [PMID: 38213551 PMCID: PMC10783428 DOI: 10.3389/ti.2023.11950] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 12/08/2023] [Indexed: 01/13/2024]
Abstract
In islet transplantation (ITx), primary graft function (PGF) or beta cell function measured early after last infusion is closely associated with long term clinical outcomes. We investigated the association between PGF and 5 year insulin independence rate in ITx and pancreas transplantation (PTx) recipients. This retrospective multicenter study included type 1 diabetes patients who underwent ITx in Lille and PTx in Nantes from 2000 to 2022. PGF was assessed using the validated Beta2-score and compared to normoglycemic control subjects. Subsequently, the 5 year insulin independence rates, as predicted by a validated PGF-based model, were compared to the actual rates observed in ITx and PTx patients. The study enrolled 39 ITx (23 ITA, 16 IAK), 209 PTx recipients (23 PTA, 14 PAK, 172 SPK), and 56 normoglycemic controls. Mean[SD] PGF was lower after ITx (ITA 22.3[5.2], IAK 24.8[6.4], than after PTx (PTA 38.9[15.3], PAK 36.8[9.0], SPK 38.7[10.5]), and lower than mean beta-cell function measured in normoglycemic control: 36.6[4.3]. The insulin independence rates observed at 5 years after PTA and PAK aligned with PGF predictions, and was higher after SPK. Our results indicate a similar relation between PGF and 5 year insulin independence in ITx and solitary PTx, shedding new light on long-term transplantation outcomes.
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Affiliation(s)
- Mikael Chetboun
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
| | - Christophe Masset
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Mehdi Maanaoui
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of Nephrology, Lille, France
| | - Frédérique Defrance
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Valéry Gmyr
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Violeta Raverdy
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
| | - Thomas Hubert
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Caroline Bonner
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Lisa Supiot
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Clarisse Kerleau
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Gilles Blancho
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Julien Branchereau
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Georges Karam
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Ismaël Chelghaf
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Aurélie Houzet
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Magali Giral
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Claire Garandeau
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - Jacques Dantal
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
- Nantes Université, Inserm, UMR 1064, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Kristell Le Mapihan
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Arnaud Jannin
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Marc Hazzan
- CHU Lille, Department of Nephrology, Lille, France
| | - Robert Caiazzo
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
| | - Julie Kerr-Conte
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Marie-Christine Vantyghem
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of Endocrinology, Diabetology and Metabolism, Lille, France
| | - Diego Cantarovich
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie clinique, CHU Nantes, Nantes, France
| | - François Pattou
- Univ Lille, U1190 - EGID, Lille, France
- Inserm, U1190, Lille, France
- Institut Pasteur de Lille, Lille, France
- CHU Lille, Department of General, Endocrine and Metabolic Surgery, Lille, France
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10
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Chen QD, Liu L, Zhao XH, Liang JB, Li SW. Challenges and opportunities in the islet transplantation microenvironment: a comprehensive summary of inflammatory cytokine, immune cells, and vascular endothelial cells. Front Immunol 2023; 14:1293762. [PMID: 38111575 PMCID: PMC10725940 DOI: 10.3389/fimmu.2023.1293762] [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: 09/13/2023] [Accepted: 11/20/2023] [Indexed: 12/20/2023] Open
Abstract
It is now understood that islet transplantation serves as a β-cell replacement therapy for type 1 diabetes. Many factors impact the survival of transplanted islets, especially those related to the microenvironment. This review explored microenvironmental components, including vascular endothelial cells, inflammatory cytokines, and immune cells, and their profound effects on post-islet transplantation survival rates. Furthermore, it revealed therapeutic strategies aimed at targeting these elements. Current evidence suggests that vascular endothelial cells are pivotal in facilitating vascularization and nutrient supply and establishing a new microcirculation network for transplanted islets. Consequently, preserving the functionality of vascular endothelial cells emerges as a crucial strategy to enhance the survival of islet transplantation. Release of cytokines will lead to activation of immune cells and production and release of further cytokines. While immune cells hold undeniable significance in regulating immune responses, their activation can result in rejection reactions. Thus, establishing immunological tolerance within the recipient's body is essential for sustaining graft functionality. Indeed, future research endeavors should be directed toward developing precise strategies for modulating the microenvironment to achieve higher survival rates and more sustained transplantation outcomes. While acknowledging certain limitations inherent to this review, it provides valuable insights that can guide further exploration in the field of islet transplantation. In conclusion, the microenvironment plays a paramount role in islet transplantation. Importantly, we discuss novel perspectives that could lead to broader clinical applications and improved patient outcomes in islet transplantation.
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Affiliation(s)
- Qi-dong Chen
- Taizhou Hospital, Zhejiang University School of Medicine, Taizhou, Zhejiang, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao-hong Zhao
- Department of Pharmacy, Taizhou Hospital, Zhejiang University , Taizhou, Zhejiang, China
| | - Jun-bo Liang
- Taizhou Hospital, Zhejiang University School of Medicine, Taizhou, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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11
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Yabe SG, Fukuda S, Nishida J, Takeda F, Okochi H. The functional maturity of grafted human pluripotent stem cell derived-islets (hSC-Islets) evaluated by the glycemic set point during blood glucose normalizing process in diabetic mice. Heliyon 2023; 9:e19972. [PMID: 37809993 PMCID: PMC10559575 DOI: 10.1016/j.heliyon.2023.e19972] [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: 05/27/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
Human pluripotent stem cell (hPSCs) derived-pancreatic islets (hSC-islets) are good candidates for cell replacement therapy for patients with diabetes as substitutes for deceased donor-derived islets, because they are pluripotent and have infinite proliferation potential. Grafted hSC-islets ameliorate hyperglycemia in diabetic mice; however, several weeks are needed to normalize the hyperglycemia. These data suggest hSC-islets require maturation, but their maturation process in vivo is not yet fully understood. In this study, we utilized two kinds of streptozotocin (STZ)-induced diabetes model mice by changing the administration timing in order to examine the time course of maturation of hSC-islets and the effects of hyperglycemia on their maturation. We found no hyperglycemia in immune-compromised mice when hSC-islets had been transplanted under their kidney capsules in advance, and STZ was administered 4 weeks after transplantation. Of note, the blood glucose levels of those mice were stably maintained under 100 mg/dl 10 weeks after transplantation; this is lower than the mouse glycemic set point (120-150 mg/dl), suggesting that hSC-islets control blood glucose levels to the human glycemic set point. We confirmed that gene expression of maturation markers of pancreatic beta cells tended to upregulate during 4 weeks after transplantation. Periodical histological analysis revealed that revascularization was observed as early as 1 week after transplantation, but reinnervation in the grafted hSC-islets was not detected at all, even 15 weeks after transplantation. In conclusion, our hSC-islets need at least 4 weeks to mature, and the human glycemic set point is a good index for evaluating ultimate maturity for hSC-islets in vivo.
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Affiliation(s)
- Shigeharu G. Yabe
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Satsuki Fukuda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Junko Nishida
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Fujie Takeda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Hitoshi Okochi
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
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12
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Jeon S, Lee YS, Oh SR, Jeong J, Lee DH, So KH, Hwang NS. Recent advances in endocrine organoids for therapeutic application. Adv Drug Deliv Rev 2023; 199:114959. [PMID: 37301512 DOI: 10.1016/j.addr.2023.114959] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/21/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
The endocrine system, consisting of the hypothalamus, pituitary, endocrine glands, and hormones, plays a critical role in hormone metabolic interactions. The complexity of the endocrine system is a significant obstacle to understanding and treating endocrine disorders. Notably, advances in endocrine organoid generation allow a deeper understanding of the endocrine system by providing better comprehension of molecular mechanisms of pathogenesis. Here, we highlight recent advances in endocrine organoids for a wide range of therapeutic applications, from cell transplantation therapy to drug toxicity screening, combined with development in stem cell differentiation and gene editing technologies. In particular, we provide insights into the transplantation of endocrine organoids to reverse endocrine dysfunctions and progress in developing strategies for better engraftments. We also discuss the gap between preclinical and clinical research. Finally, we provide future perspectives for research on endocrine organoids for the development of more effective treatments for endocrine disorders.
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Affiliation(s)
- Suwan Jeon
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Sun Lee
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Seh Ri Oh
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Jinseong Jeong
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Dong-Hyun Lee
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyoung-Ha So
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University, Seoul 08826, Republic of Korea.
| | - Nathaniel S Hwang
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea; School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University, Seoul 08826, Republic of Korea; Institute of Engineering Research, Seoul National University, Seoul, 08826, Republic of Korea.
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13
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Qin T, Smink AM, de Vos P. Enhancing longevity of immunoisolated pancreatic islet grafts by modifying both the intracapsular and extracapsular environment. Acta Biomater 2023:S1742-7061(23)00362-8. [PMID: 37392934 DOI: 10.1016/j.actbio.2023.06.038] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/02/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease characterized by autoimmune destruction of pancreatic β cells. Transplantation of immunoisolated pancreatic islets might treat T1DM in the absence of chronic immunosuppression. Important advances have been made in the past decade as capsules can be produced that provoke minimal to no foreign body response after implantation. However, graft survival is still limited as islet dysfunction may occur due to chronic damage to islets during islet isolation, immune responses induced by inflammatory cells, and nutritional issues for encapsulated cells. This review summarizes the current challenges for promoting longevity of grafts. Possible strategies for improving islet graft longevity are also discussed, including supplementation of the intracapsular milieu with essential survival factors, promotion of vascularization and oxygenation near capsules, modulation of biomaterials, and co-transplantation of accessory cells. Current insight is that both the intracapsular as well as the extracapsular properties should be improved to achieve long-term survival of islet-tissue. Some of these approaches reproducibly induce normoglycemia for more than a year in rodents. Further development of the technology requires collective research efforts in material science, immunology, and endocrinology. STATEMENT OF SIGNIFICANCE: Islet immunoisolation allows for transplantation of insulin producing cells in absence of immunosuppression and might facilitate the use of xenogeneic cell sources or grafting of cells obtained from replenishable cell sources. However, a major challenge to date is to create a microenvironment that supports long-term graft survival. This review provides a comprehensive overview of the currently identified factors that have been demonstrated to be involved in either stimulating or reducing islet graft survival in immunoisolating devices and discussed current strategies to enhance the longevity of encapsulated islet grafts as treatment for type 1 diabetes. Although significant challenges remain, interdisciplinary collaboration across fields may overcome obstacles and facilitate the translation of encapsulated cell therapy from the laboratory to clinical application.
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Affiliation(s)
- Tian Qin
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, The Netherlands.
| | - Alexandra M Smink
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, The Netherlands
| | - Paul de Vos
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, EA 11, 9713 GZ, Groningen, The Netherlands
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14
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Chetboun M, Drumez E, Ballou C, Maanaoui M, Payne E, Barton F, Kerr-Conte J, Vantyghem MC, Piemonti L, Rickels MR, Labreuche J, Pattou F. Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry. Lancet Diabetes Endocrinol 2023; 11:391-401. [PMID: 37105208 PMCID: PMC10388704 DOI: 10.1016/s2213-8587(23)00082-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/04/2023] [Accepted: 03/06/2023] [Indexed: 04/29/2023]
Abstract
BACKGROUND Allogeneic islet transplantation is a validated therapy in type 1 diabetes; however, there is decline of transplanted islet graft function over time and the mechanisms underlying this decline are unclear. We evaluated the distinct association between primary graft function (PGF) and 5-year islet transplantation outcomes. METHODS In this retrospective, multicentre, observational cohort study, we enrolled all patients from the Collaborative Islet Transplant Registry who received islet transplantation alone (ITA recipients) or islet-after-kidney transplantation (IAK recipients) between Jan 19, 1999, and July 17, 2020, with a calculable PGF (exposure of interest), measured 28 days after last islet infusion with a validated composite index of islet graft function (BETA-2 score). The primary outcome was cumulative incidence of unsuccessful islet transplantation, defined as an HbA1c of 7·0% (53 mmol/mol) or higher, or severe hypoglycaemia (ie, requiring third-party intervention to correct), or a fasting C-peptide concentration of less than 0·2 ng/mL. Secondary outcomes were graft exhaustion (fasting C-peptide <0·3 ng/mL); inadequate glucose control (HbA1c ≥7·0% [53 mmol/mol] or severe hypoglycaemia); and requirement for exogenous insulin therapy (≥14 consecutive days). Associations between PGF and islet transplantation outcomes were explored with a competing risk analysis adjusted for all covariates suspected or known to affect outcomes. A predictive model based on PGF was built and internally validated by using bootstraps resampling method. FINDINGS In 39 centres worldwide, we enrolled 1210 patients with a calculable PGF (of those without missing data, mean age 47 years [SD 10], 712 [59·5%] were female, and 865 (97·9%) were White), who received a median of 10·8 thousand islet-equivalents per kg of bodyweight (IQR 7·4-13·5). 986 (82·4%) were ITA recipients and 211 (17·6%) were IAK recipients. Of 1210 patients, 452 (37·4%) received a single islet infusion and 758 (62·6%) received multiple islet infusions. Mean PGF was 14·3 (SD 8·8). The 5-year cumulative incidence of unsuccessful islet transplantation was 70·7% (95% CI 67·2-73·9), and was inversely and linearly related to PGF, with an adjusted subhazard ratio (sHR) of 0·77 (95% CI 0·72-0·82) per 5-unit increase of BETA-2 score (p<0·0001). Secondary endpoints were similarly related to PGF. The model-adjusted median C-statistic values of PGF for predicting 5-year cumulative incidences of unsuccessful islet transplantation, graft exhaustion, inadequate glucose control, and exogenous insulin therapy were 0·70 (range 0·69-0·71), 0·76 (0·74-0·77), 0·65 (0·64-0·66), and 0·72 (0·71-0·73), respectively. INTERPRETATION This global multicentre study reports a linear and independent association between PGF and 5-year clinical outcomes of islet transplantation. The main study limitations are its retrospective design and the absence of analysis of complications. FUNDING Public Health Service Research, National Institutes of Health, Juvenile Diabetes Research Foundation International, Agence National de la Recherche, Fondation de l'Avenir, and Fonds de Dotation Line Renaud-Loulou Gasté.
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Affiliation(s)
- Mikaël Chetboun
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of General and Endocrine Surgery, Lille, France
| | - Elodie Drumez
- CHU Lille, ULR 2694 Évaluation des technologies de santé et des pratiques médicales (METRICS), Lille, France
| | - Cassandra Ballou
- Collaborative Islet Transplant Registry, The EMMES Company, Rockville, MD, USA
| | - Mehdi Maanaoui
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of Nephrology, Lille, France
| | - Elizabeth Payne
- Collaborative Islet Transplant Registry, The EMMES Company, Rockville, MD, USA
| | - Franca Barton
- Collaborative Islet Transplant Registry, The EMMES Company, Rockville, MD, USA
| | - Julie Kerr-Conte
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France
| | - Marie-Christine Vantyghem
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of Endocrinology, Diabetology, and Metabolism, Lille, France
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS, Ospedale San Raffaele, 20132 Milan, Italy
| | - Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Julien Labreuche
- CHU Lille, ULR 2694 Évaluation des technologies de santé et des pratiques médicales (METRICS), Lille, France
| | - François Pattou
- Université Lille, U1190 Translational Research for Diabetes, INSERM, Institut Pasteur de Lille, Lille, France; CHU Lille, Department of General and Endocrine Surgery, Lille, France.
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15
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4-OI Protects MIN6 Cells from Oxidative Stress Injury by Reducing LDHA-Mediated ROS Generation. Biomolecules 2022; 12:biom12091236. [PMID: 36139075 PMCID: PMC9496514 DOI: 10.3390/biom12091236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic beta cells are highly susceptible to oxidative stress, which plays a crucial role in diabetes outcomes. Progress has been slow to identify molecules that could be utilized to enhance cell survival and function under oxidative stress. Itaconate, a byproduct of the tricarboxylic acid cycle, has both anti-inflammatory and antioxidant properties. The effects of itaconate on beta cells under oxidative stress are relatively unknown. We explored the effects of 4-octyl itaconate—a cell-permeable derivative of itaconate—on MIN6 (a beta cell model) under oxidative stress conditions caused by hypoxia, along with its mechanism of action. Treatment with 4-OI reversed hypoxia-induced cell death, reduced ROS production, and inhibited cell death pathway activation and inflammatory cytokine secretion in MIN6 cells. The 4-OI treatment also suppressed lactate dehydrogenase A (LDHA)activity, which increases under hypoxia. Treatment of cells with the ROS scavenger NAC and LDHA-specific inhibitor FX-11 reproduced the beneficial effects of 4-OI on MIN6 cell viability under oxidative stress conditions, confirming its role in regulating ROS production. Conversely, overexpression of LDHA reduced the beneficial effects exerted by 4-OI on cells. Our findings provide a strong rationale for using 4-OI to prevent the death of MIN6 cells under oxidative stress.
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16
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Ilegems E, Berggren PO. The Eye as a Transplantation Site to Monitor Pancreatic Islet Cell Plasticity. Front Endocrinol (Lausanne) 2021; 12:652853. [PMID: 33967961 PMCID: PMC8104082 DOI: 10.3389/fendo.2021.652853] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/26/2021] [Indexed: 02/05/2023] Open
Abstract
The endocrine cells confined in the islets of Langerhans are responsible for the maintenance of blood glucose homeostasis. In particular, beta cells produce and secrete insulin, an essential hormone regulating glucose uptake and metabolism. An insufficient amount of beta cells or defects in the molecular mechanisms leading to glucose-induced insulin secretion trigger the development of diabetes, a severe disease with epidemic spreading throughout the world. A comprehensive appreciation of the diverse adaptive procedures regulating beta cell mass and function is thus of paramount importance for the understanding of diabetes pathogenesis and for the development of effective therapeutic strategies. While significant findings were obtained by the use of islets isolated from the pancreas, in vitro studies are inherently limited since they lack the many factors influencing pancreatic islet cell function in vivo and do not allow for longitudinal monitoring of islet cell plasticity in the living organism. In this respect a number of imaging methodologies have been developed over the years for the study of islets in situ in the pancreas, a challenging task due to the relatively small size of the islets and their location, scattered throughout the organ. To increase imaging resolution and allow for longitudinal studies in individual islets, another strategy is based on the transplantation of islets into other sites that are more accessible for imaging. In this review we present the anterior chamber of the eye as a transplantation and imaging site for the study of pancreatic islet cell plasticity, and summarize the major research outcomes facilitated by this technological platform.
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Affiliation(s)
- Erwin Ilegems
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institute, Stockholm, Sweden
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Center for Diabetes and Metabolism Research, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
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17
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Wang Y, Wang JW, Li Y, Tian XH, Feng XS, Zhang SC, Liu PJ, Xue WJ, Zheng J, Ding XM. Bone marrow-derived mesenchymal stem cells improve rat islet graft revascularization by upregulating ISL1. STEM CELLS (DAYTON, OHIO) 2021; 39:1033-1048. [PMID: 33754392 DOI: 10.1002/stem.3378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 03/01/2021] [Indexed: 11/12/2022]
Abstract
Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in islet transplantation.
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Affiliation(s)
- Ying Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Jing-Wen Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yang Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xiao-Hui Tian
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xin-Shun Feng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Shu-Cong Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Pei-Jun Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Wu-Jun Xue
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xiao-Ming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
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The vascular architecture of the pancreatic islets: A homage to August Krogh. Comp Biochem Physiol A Mol Integr Physiol 2021; 252:110846. [DOI: 10.1016/j.cbpa.2020.110846] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 01/15/2023]
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19
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Chung WY, Pollard CA, Kumar R, Drogemuller CJ, Naziruddin B, Stover C, Issa E, Isherwood J, Cooke J, Levy MF, Coates PTH, Garcea G, Dennison AR. A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:98. [PMID: 33569400 PMCID: PMC7867892 DOI: 10.21037/atm-20-3519] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background The initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation. Methods Inflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls. Results The peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1β (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent. Conclusions The cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.
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Affiliation(s)
- Wen Yuan Chung
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Cristina A Pollard
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Rohan Kumar
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | | | | | - Cordula Stover
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
| | - Eyad Issa
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - John Isherwood
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Jill Cooke
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Marlon F Levy
- Baylor Research Institute, Dallas & Fort Worth, TX, USA
| | - P Toby H Coates
- Australian Islet Consortium, Royal Adelaide Hospital, South Australia, Australia
| | - Giuseppe Garcea
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
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20
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Cayabyab F, Nih LR, Yoshihara E. Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes. Front Endocrinol (Lausanne) 2021; 12:732431. [PMID: 34589059 PMCID: PMC8473744 DOI: 10.3389/fendo.2021.732431] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/13/2021] [Indexed: 01/08/2023] Open
Abstract
Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.
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Affiliation(s)
- Fritz Cayabyab
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
| | - Lina R. Nih
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
- David Geffen School of Medicine at University of California, Los Angeles, CA, United States
| | - Eiji Yoshihara
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
- David Geffen School of Medicine at University of California, Los Angeles, CA, United States
- *Correspondence: Eiji Yoshihara,
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21
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Fuchs S, Ernst AU, Wang LH, Shariati K, Wang X, Liu Q, Ma M. Hydrogels in Emerging Technologies for Type 1 Diabetes. Chem Rev 2020; 121:11458-11526. [DOI: 10.1021/acs.chemrev.0c01062] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Stephanie Fuchs
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Alexander U. Ernst
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Long-Hai Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Kaavian Shariati
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Xi Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Qingsheng Liu
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Minglin Ma
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
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22
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Caserto JS, Bowers DT, Shariati K, Ma M. Biomaterial Applications in Islet Encapsulation and Transplantation. ACS APPLIED BIO MATERIALS 2020; 3:8127-8135. [DOI: 10.1021/acsabm.0c01235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Julia S. Caserto
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Daniel T. Bowers
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Kaavian Shariati
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
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23
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Methacrylic acid copolymer coating of polypropylene mesh chamber improves subcutaneous islet engraftment. Biomaterials 2020; 259:120324. [DOI: 10.1016/j.biomaterials.2020.120324] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023]
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24
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Sthijns MMJPE, Jetten MJ, Mohammed SG, Claessen SMH, de Vries RHW, Stell A, de Bont DFA, Engelse MA, Mumcuoglu D, van Blitterswijk CA, Dankers PYW, de Koning EJP, van Apeldoorn AA, LaPointe VLS. Oxidative stress in pancreatic alpha and beta cells as a selection criterion for biocompatible biomaterials. Biomaterials 2020; 267:120449. [PMID: 33129188 DOI: 10.1016/j.biomaterials.2020.120449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 10/06/2020] [Accepted: 10/10/2020] [Indexed: 12/12/2022]
Abstract
The clinical success rate of islet transplantation, namely independence from insulin injections, is limited by factors that lead to graft failure, including inflammation, acute ischemia, acute phase response, and insufficient vascularization. The ischemia and insufficient vascularization both lead to high levels of oxidative stress, which are further aggravated by islet encapsulation, inflammation, and undesirable cell-biomaterial interactions. To identify biomaterials that would not further increase damaging oxidative stress levels and that are also suitable for manufacturing a beta cell encapsulation device, we studied five clinically approved polymers for their effect on oxidative stress and islet (alpha and beta cell) function. We found that 300 poly(ethylene oxide terephthalate) 55/poly(butylene terephthalate) 45 (PEOT/PBT300) was more resistant to breakage and more elastic than other biomaterials, which is important for its immunoprotective function. In addition, it did not induce oxidative stress or reduce viability in the MIN6 beta cell line, and even promoted protective endogenous antioxidant expression over 7 days. Importantly, PEOT/PBT300 is one of the biomaterials we studied that did not interfere with insulin secretion in human islets.
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Affiliation(s)
- Mireille M J P E Sthijns
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Marlon J Jetten
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Sami G Mohammed
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Sandra M H Claessen
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Rick H W de Vries
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Adam Stell
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Denise F A de Bont
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Marten A Engelse
- Department of Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands
| | - Didem Mumcuoglu
- Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, the Netherlands
| | - Clemens A van Blitterswijk
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Patricia Y W Dankers
- Department of Biomedical Engineering, and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, the Netherlands
| | - Eelco J P de Koning
- Department of Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands; Hubrecht Institute, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
| | - Aart A van Apeldoorn
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands
| | - Vanessa L S LaPointe
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, the Netherlands.
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25
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Zhang L, Miao H, Wang D, Qiu H, Zhu Y, Yao X, Guo Y, Wang Z. Pancreatic extracellular matrix and platelet-rich plasma constructing injectable hydrogel for pancreas tissue engineering. Artif Organs 2020; 44:e532-e551. [PMID: 32671848 DOI: 10.1111/aor.13775] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 06/11/2020] [Accepted: 07/06/2020] [Indexed: 12/13/2022]
Abstract
The development of pancreatic extracellular matrices enriched with insulin-secreting β-cells is a promising tissue engineering approach to treat type 1 diabetes. However, its long-term therapeutic efficacy is restricted by the defensive mechanism of host immune response and the lack of developed vascularization as appropriate after transplantation. Platelet-rich plasma (PRP), as an autologous platelet concentrate, contains a large number of active factors that are essential for the cell viability, vascularization, and immune regulation. In this study, we have incorporated pancreatic extracellular matrix (PEM) with PRP to develop a three-dimensional (3D) injectable PEM-PRP hydrogel to coculture and transplant rat insulinoma cells (INS-1) and human umbilical vein endothelial cells (HUVECs). Results from this study demonstrated that PEM-PRP hydrogel mimicked the biochemical compositions of native extracellular matrices, and possessed the enhanced elastic modulus and resistance to enzymatic degradation that enabled biomaterials to maintain its volume and slowly degrade. Additionally, PEM-PRP hydrogel could release growth factors in a sustained manner. In vitro, PEM-PRP hydrogel significantly promoted the viability, insulin-secreting function, and insulin gene expression of gel encapsulated INS-1 cells. Moreover, HUVECs encapsulated in PEM-PRP hydrogel were found to constitute many lumen-like structures and exhibited high expression of proangiogenic genes. In vivo transplantation of PEM-PRP hydrogel encapsulated with INS-1 cells and HUVECs improved the viability of INS-1 cells, promoted vascularization, inhibited the host inflammatory response, and reversed hyperglycemia of diabetic rats. Our study suggests that the PEM-PRP hydrogel offers excellent biocompatibility and proangiogenic property, and may serve as an effective biomaterial platform to maintain the long-term survival and function of insulin-secreting β cells.
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Affiliation(s)
- Liang Zhang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P.R. China.,Department of General Surgery, Tengzhou Central People's Hospital, Tengzhou, P.R. China
| | - Haiyan Miao
- Department of General Surgery, The Sixth People's Hospital, Nantong, P.R. China
| | - Dongzhi Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P.R. China.,Research Center of Clinical Medical, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Hongquan Qiu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P.R. China.,Research Center of Clinical Medical, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Yi Zhu
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P.R. China.,Research Center of Clinical Medical, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Xihao Yao
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P.R. China.,Research Center of Clinical Medical, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Yibing Guo
- Research Center of Clinical Medical, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Zhiwei Wang
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P.R. China
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26
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Figueiredo H, Figueroa ALC, Garcia A, Fernandez-Ruiz R, Broca C, Wojtusciszyn A, Malpique R, Gasa R, Gomis R. Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes. Sci Transl Med 2020; 11:11/497/eaar6294. [PMID: 31217339 DOI: 10.1126/scitranslmed.aar6294] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 01/16/2019] [Accepted: 05/23/2019] [Indexed: 12/12/2022]
Abstract
Deficient vascularization is a major driver of early islet graft loss and one of the primary reasons for the failure of islet transplantation as a viable treatment for type 1 diabetes. This study identifies the protein tyrosine phosphatase 1B (PTP1B) as a potential modulator of islet graft revascularization. We demonstrate that grafts of pancreatic islets lacking PTP1B exhibit increased revascularization, which is accompanied by improved graft survival and function, and recovery of normoglycemia and glucose tolerance in diabetic mice transplanted with PTP1B-deficient islets. Mechanistically, we show that the absence of PTP1B leads to activation of hypoxia-inducible factor 1α-independent peroxisome proliferator-activated receptor γ coactivator 1α/estrogen-related receptor α signaling and enhanced expression and production of vascular endothelial growth factor A (VEGF-A) by β cells. These observations were reproduced in human islets. Together, these findings reveal that PTP1B regulates islet VEGF-A production and suggest that this phosphatase could be targeted to improve islet transplantation outcomes.
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Affiliation(s)
- Hugo Figueiredo
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain.,University of Barcelona, 08036 Barcelona, Spain.,Escuela de Medicina y Ciencias de la Salud, Dept. Medicina Cardiovascular y Metabolómica, Tecnológico de Monterrey, 66278 San Pedro Garza García, Nuevo León, Mexico
| | - Ana Lucia C Figueroa
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain.,University of Barcelona, 08036 Barcelona, Spain
| | - Ainhoa Garcia
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Rebeca Fernandez-Ruiz
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Christophe Broca
- CHU Montpellier, Laboratory of Cell Therapy for Diabetes (LTCD), Hospital St-Eloi, 34295 Montpellier, France
| | - Anne Wojtusciszyn
- CHU Montpellier, Laboratory of Cell Therapy for Diabetes (LTCD), Hospital St-Eloi, 34295 Montpellier, France.,Department of Endocrinology, Diabetes and Nutrition, University Hospital of Montpellier, Lapeyronie Hospital, 34295 Montpellier, France.,Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland
| | - Rita Malpique
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
| | - Rosa Gasa
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Ramon Gomis
- Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain. .,University of Barcelona, 08036 Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.,Universitat Oberta de Catalunya (UOC), 08018 Barcelona, Spain.,Department of Endocrinology and Nutrition, Hospital Clinic of Barcelona, 08036 Barcelona, Spain
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27
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NLRP3 Inflammasome is Activated in Rat Pancreatic Islets by Transplantation and Hypoxia. Sci Rep 2020; 10:7011. [PMID: 32332867 PMCID: PMC7181690 DOI: 10.1038/s41598-020-64054-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 04/10/2020] [Indexed: 01/14/2023] Open
Abstract
Hypoxia, IL-1β production and oxidative stress are involved in islet graft dysfunction and destruction. However, the link between these events has not yet been determined in transplanted islets. The goal of this study was to determine whether NLRP3 inflammasome is responsible for IL-1β production and if it is activated by hypoxia-induced oxidative stress in transplanted islets. Rat islets were transplanted under the kidney capsule of immunodeficient mice. At different times post-transplantation, blood samples were collected and islet grafts harvested. Rat islets were also incubated in vitro either under normoxia or hypoxia for 24 h, in the absence or presence of inhibitors of NLRP3 inflammasome (CASP1 inhibitor) or oxidative stress (NAC). NLRP3, CASP1, IL1B, BBC3 pro-apoptotic and BCL2 anti-apoptotic genes in transplanted and in vitro incubated islets were then studied using real time PCR. IL-1β released in the blood and in the supernatant was quantified by ELISA. Cell death was analysed by propidium iodide and Annexin-V staining. NLRP3, CASP1 and BBC3 in transplanted rat islets and IL-1β in blood transiently increased during the first days after transplantation. In islets incubated under hypoxia, NRLP3, IL1B and CASP1 and IL-1β released in supernatant increased compared to islets incubated under normoxia. These effects were prevented by the inhibition of NLRP3 inflammasome by CASP1 or oxidative stress by NAC. However, these inhibitors did not prevent hypoxia-induced rat islet death. These data show that NLRP3 inflammasome in rat islets is transiently activated after their transplantation and induced through oxidative stress in vitro. However, NRLP3 inflammasome inhibition does not protect islet cells against hypoxia.
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Vlahos AE, Kinney SM, Kingston BR, Keshavjee S, Won SY, Martyts A, Chan WC, Sefton MV. Endothelialized collagen based pseudo-islets enables tuneable subcutaneous diabetes therapy. Biomaterials 2020; 232:119710. [DOI: 10.1016/j.biomaterials.2019.119710] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 10/25/2022]
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29
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Delaune V, Toso C, Kahler-Quesada A, Slits F, Gex Q, Kaya G, Lavallard V, Orci LA, Peloso A, Lacotte S. Antibody-induced NKG2D blockade in a rat model of intraportal islet transplantation leads to a deleterious reaction. Transpl Int 2020; 33:675-688. [PMID: 32003082 DOI: 10.1111/tri.13589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/04/2019] [Accepted: 01/28/2020] [Indexed: 11/30/2022]
Abstract
Intraportal islet transplantation is plagued by an acute destruction of transplanted islets. Amongst the first responders, NK cells and macrophages harbour an activating receptor, NKG2D, recognizing ligands expressed by stressed cells. We aimed to determine whether islet NKG2D ligand expression increases with culture time, and to analyse the impact of antibody-induced NKG2D blockade in islet transplantation. NKG2D-ligand expression was analysed in rat and human islets. Syngeneic marginal mass intraportal islet transplantations were performed in rats: control group, recipients transplanted with NKG2D-recombinant-treated islets (recombinant group), and recipients treated with a mouse anti-rat anti-NKG2D antibody and transplanted with recombinant-treated islets (antibody-recombinant group). Islets demonstrated increased gene expression of NKG2D ligands with culture time. Blockade of NKG2D on NK cells decreased in vitro cytotoxicity against islets. Recipients from the control and recombinant groups showed similar metabolic results; conversely, treatment with the antibody resulted in lower diabetes reversal. The antibody depleted circulating and liver NK cells in recipients, who displayed increased macrophage infiltration of recipient origin around the transplanted islets. In vitro blockade of NKG2D ligands had no impact on early graft function. Systemic treatment of recipients with an anti-NKG2D antibody was deleterious to the islet graft, possibly through an antibody-dependent cell-mediated cytotoxicity reaction.
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Affiliation(s)
- Vaihere Delaune
- Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland.,Hepatology and Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Toso
- Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland.,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
| | - Florence Slits
- 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
| | - Gürkan Kaya
- Division of Dermatology and Venereology, Department of Internal Medicine Specialties, Geneva University Hospitals, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Transplantation Laboratory, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Lorenzo Annibale Orci
- Divisions of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland.,Hepatology and 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.,Hepatology and 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
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30
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Insulin-producing organoids engineered from islet and amniotic epithelial cells to treat diabetes. Nat Commun 2019; 10:4491. [PMID: 31582751 PMCID: PMC6776618 DOI: 10.1038/s41467-019-12472-3] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 09/12/2019] [Indexed: 12/13/2022] Open
Abstract
Maintaining long-term euglycemia after intraportal islet transplantation is hampered by the considerable islet loss in the peri-transplant period attributed to inflammation, ischemia and poor angiogenesis. Here, we show that viable and functional islet organoids can be successfully generated from dissociated islet cells (ICs) and human amniotic epithelial cells (hAECs). Incorporation of hAECs into islet organoids markedly enhances engraftment, viability and graft function in a mouse type 1 diabetes model. Our results demonstrate that the integration of hAECs into islet cell organoids has great potential in the development of cell-based therapies for type 1 diabetes. Engineering of functional mini-organs using this strategy will allow the exploration of more favorable implantation sites, and can be expanded to unlimited (stem-cell-derived or xenogeneic) sources of insulin-producing cells. Islet transplantation is a feasible approach to treat type I diabetes, however inflammation and poor vascularisation impair long-term engraftment. Here the authors show that incorporating human amniotic epithelial cells into islet organoids improves engraftment and function of organoids, through enhanced revascularisation.
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Nagaya M, Hayashi A, Nakano K, Honda M, Hasegawa K, Okamoto K, Itazaki S, Matsunari H, Watanabe M, Umeyama K, Nagashima H. Distributions of endocrine cell clusters during porcine pancreatic development. PLoS One 2019; 14:e0216254. [PMID: 31075154 PMCID: PMC6510474 DOI: 10.1371/journal.pone.0216254] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 04/16/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Pancreatic islet xenotransplantation is a potential treatment for diabetes mellitus, and porcine pancreas may provide a readily available source of islets. Islets in juvenile pigs are smaller than those in young adult pigs, but the insulin content is very similar. In addition, as juvenile pigs are more easily reared in uncontaminated conditions, many researchers have conducted studies using pancreatic islets from juvenile pigs. We aimed to analyze the distributions of endocrine cell clusters by comprehensively evaluating juvenile porcine pancreatic development and to propose an appropriate age at which islets could be isolated from the juvenile porcine pancreas. METHODS Splenic (SL) and duodenal lobe (DL) samples were collected from the pancreases of pigs aged 0-180 days (n = 3/day after birth). The chronological changes in endocrine cell clustering were analyzed in relation to morphological changes, cell characterization, numbers, islet areas, and gene expression. RESULTS In juvenile pigs aged 0-21 days, the pancreas contained numerous endocrine cells, and compact islets appeared from 21 days of age. Well-defined small islets were seen at 28 days of age, and the clusters were denser in the SL than in the DL. At 35 days of age, the islets were morphologically similar to those observed at 180 days of age, and the greater number of islets was similar to that seen at 90 days of age. The differences in the islets' cytoarchitecture between the lobes were negligible. The expression of β-cell-related genes was higher in the juvenile pancreas than in the adult pancreas, and the expression of neurogenin-3 decreased dramatically over time. CONCLUSIONS These findings may have implications for attempts to refine the most appropriate age for islet isolation from porcine donors. Focusing on porcine pancreatic islets isolated at around 35 days after birth may offer benefits regarding their xenotransplantation potential.
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Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
- Department of Immunology, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Japan
| | - Asuka Hayashi
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Michiyo Honda
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
| | - Koki Hasegawa
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazutoshi Okamoto
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Shiori Itazaki
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
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Jansson L, Carlsson PO. Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans. Compr Physiol 2019; 9:799-837. [PMID: 30892693 DOI: 10.1002/cphy.c160050] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The pancreatic islets are more richly vascularized than the exocrine pancreas, and possess a 5- to 10-fold higher basal and stimulated blood flow, which is separately regulated. This is reflected in the vascular anatomy of the pancreas where islets have separate arterioles. There is also an insulo-acinar portal system, where numerous venules connect each islet to the acinar capillaries. Both islets and acini possess strong metabolic regulation of their blood perfusion. Of particular importance, especially in the islets, is adenosine and ATP/ADP. Basal and stimulated blood flow is modified by local endothelial mediators, the nervous system as well as gastrointestinal hormones. Normally the responses to the nervous system, especially the parasympathetic and sympathetic nerves, are fairly similar in endocrine and exocrine parts. The islets seem to be more sensitive to the effects of endothelial mediators, especially nitric oxide, which is a permissive factor to maintain the high basal islet blood flow. The gastrointestinal hormones with pancreatic effects mainly influence the exocrine pancreatic blood flow, whereas islets are less affected. A notable exception is incretin hormones and adipokines, which preferentially affect islet vasculature. Islet hormones can influence both exocrine and endocrine blood vessels, and these complex effects are discussed. Secondary changes in pancreatic and islet blood flow occur during several conditions. To what extent changes in blood perfusion may affect the pathogenesis of pancreatic diseases is discussed. Both type 2 diabetes mellitus and acute pancreatitis are conditions where we think there is evidence that blood flow may contribute to disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:799-837, 2019.
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Affiliation(s)
- Leif Jansson
- Uppsala University, Department of Medical Cell Biology, Uppsala, Sweden
| | - Per-Ola Carlsson
- Uppsala University, Department of Medical Cell Biology, Uppsala, Sweden.,Uppsala University, Department of Medical Sciences, Uppsala, Sweden
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Local release of rapamycin by microparticles delays islet rejection within the anterior chamber of the eye. Sci Rep 2019; 9:3918. [PMID: 30850640 PMCID: PMC6408557 DOI: 10.1038/s41598-019-40404-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 02/14/2019] [Indexed: 12/23/2022] Open
Abstract
The anterior chamber of the eye (ACE) has emerged as a promising clinical islet transplantation site because of its multiple advantages over the conventional intra-hepatic portal site. This includes reduced surgical invasiveness and increased islet graft survival rate. It also allows for enhanced accessibility and monitoring of the islets. Although the ACE is initially an immuno-privileged site, this privilege is disrupted once the islet grafts are re-vascularized. Given that the ACE is a confined space, achieving graft immune tolerance through local immunosuppressive drug delivery is therefore feasible. Here, we show that islet rejection in the ACE of mice can be significantly suppressed through local delivery of rapamycin by carefully designed sustained-release microparticles. In this 30-day study, allogeneic islet grafts with blank microparticles were completely rejected 18 days post-transplantation into mice. Importantly, allogeneic islet grafts co-injected with rapamycin releasing microparticles into a different eye of the same recipient were preserved much longer, with some grafts surviving for more than 30 days. Hence, islet allograft survival was enhanced by a localized and prolonged delivery of an immunosuppressive drug. We envisage that this procedure will relieve diabetic transplant recipients from harsh systemic immune suppression, while achieving improved glycemic control and reduced insulin dependence.
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34
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Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy. Cell Metab 2019; 29:545-563. [PMID: 30840911 DOI: 10.1016/j.cmet.2019.02.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 02/12/2019] [Accepted: 02/13/2019] [Indexed: 12/23/2022]
Abstract
Incredible strides have been made since the discovery of insulin almost 100 years ago. Insulin formulations have improved dramatically, glucose levels can be measured continuously, and recently first-generation biomechanical "artificial pancreas" systems have been approved by regulators around the globe. However, still only a small fraction of patients with diabetes achieve glycemic goals. Replacement of insulin-producing cells via transplantation shows significant promise, but is limited in application due to supply constraints (cadaver-based) and the need for chronic immunosuppression. Over the past decade, significant progress has been made to address these barriers to widespread implementation of a cell therapy. Can glucose levels in people with diabetes be normalized with artificial pancreas systems or via cell replacement approaches? Here we review the road ahead, including the challenges and opportunities of both approaches.
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35
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Ren G, Rezaee M, Razavi M, Taysir A, Wang J, Thakor AS. Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties. Cell Tissue Res 2019; 376:353-364. [PMID: 30707291 DOI: 10.1007/s00441-019-02997-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/17/2019] [Indexed: 02/07/2023]
Abstract
A significant proportion of islets are lost following transplantation due to hypoxia and inflammation. We hypothesize that adipose tissue-derived mesenchymal stem cells (AD-MSCs) can rescue a sub-therapeutic number of transplanted islets by helping them establish a new blood supply and reducing inflammation. Diabetic mice received syngeneic transplantation with 75 (minimal), 150 (sub-therapeutic), or 225 (therapeutic) islets, with or without 1 × 106 mouse AD-MSCs. Fasting blood glucose (FBG) values were measured over 6 weeks with tissue samples collected for islet structure and morphology (H&E, insulin/glucagon staining). Histological and immunohistochemical analyses of islets were also performed at 2 weeks in animals transplanted with a sub-therapeutic number of islets, with and without AD-MSCs, to determine new blood vessel formation, the presence of pro-angiogenic factors facilitating revascularization, and the degree of inflammation. AD-MSCs had no beneficial effect on FBG values when co-transplanted with a minimal or therapeutic number of islets. However, AD-MSCs significantly reduced FBG values and restored glycemic control in diabetic animals transplanted with a sub-therapeutic number of islets. Islets co-transplanted with AD-MSCs preserved their native morphology and organization and exhibited less aggregation when compared to islets transplanted alone. In the sub-therapeutic group, AD-MSCs significantly increased islet revascularization and the expression of angiogenic factors including hepatocyte growth factor (HGF) and angiopoietin-1 (Ang-1) while also reducing inflammation. AD-MSCs can rescue the function of islets when transplanted in a sub-therapeutic number, for at least 6 weeks, via their ability to maintain islet architecture while concurrently facilitating islet revascularization and reducing inflammation.
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Affiliation(s)
- Gang Ren
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Melika Rezaee
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA.,Chicago Medical School, Rosalind Franklin University, North Chicago, IL, 60064, USA
| | - Mehdi Razavi
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Ahmed Taysir
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA.
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36
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Mouré A, Bacou E, Bosch S, Jegou D, Salama A, Riochet D, Gauthier O, Blancho G, Soulillou J, Poncelet D, Olmos E, Bach J, Mosser M. Extracellular hemoglobin combined with an O
2
‐generating material overcomes O
2
limitation in the bioartificial pancreas. Biotechnol Bioeng 2019; 116:1176-1189. [DOI: 10.1002/bit.26913] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/05/2018] [Accepted: 12/26/2018] [Indexed: 12/29/2022]
Affiliation(s)
- Anne Mouré
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
| | - Elodie Bacou
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
| | - Steffi Bosch
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
| | - Dominique Jegou
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
| | - Apolline Salama
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
- Centre de Recherche en Transplantation et Immunologie UMR 1064INSERM, Université de NantesNantes France
| | - David Riochet
- Service de Pédiatrie des Maladies ChroniquesCHU de NantesNantes France
| | | | - Gilles Blancho
- Centre de Recherche en Transplantation et Immunologie UMR 1064INSERM, Université de NantesNantes France
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU NantesNantes France
| | - Jean‐Paul Soulillou
- Centre de Recherche en Transplantation et Immunologie UMR 1064INSERM, Université de NantesNantes France
- Institut de Transplantation Urologie Néphrologie (ITUN), CHU NantesNantes France
| | - Denis Poncelet
- Department of Process Engineering for Environment and Food Laboratory (GEPEA)UMR CNRS 6144, OnirisNantes France
| | - Eric Olmos
- Laboratoire Réactions et Génie des Procédés (LRGP)Université de Lorraine, CNRSNancy France
| | - Jean‐Marie Bach
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
| | - Mathilde Mosser
- Immuno-Endocrinology Unit (IECM), Oniris, INRA, Université Bretagne LoireNantes France
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37
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Biofabrication of a vascularized islet organ for type 1 diabetes. Biomaterials 2019; 199:40-51. [PMID: 30735895 DOI: 10.1016/j.biomaterials.2019.01.035] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/27/2018] [Accepted: 01/18/2019] [Indexed: 12/17/2022]
Abstract
Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.
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38
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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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39
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Abstract
PURPOSE OF REVIEW Engineering endocrine pancreatic tissue is an emerging topic in type 1 diabetes with the intent to overcome the current limitation of β cell transplantation. During islet isolation, the vascularized structure and surrounding extracellular matrix (ECM) are completely disrupted. Once implanted, islets slowly engraft and mostly are lost for the initial avascular phase. This review discusses the main building blocks required to engineer the endocrine pancreas: (i) islet niche ECM, (ii) islet niche vascular network, and (iii) new available sources of endocrine cells. RECENT FINDINGS Current approaches include the following: tissue engineering of endocrine grafts by seeding of native or synthetic ECM scaffolds with human islets, vascularization of native or synthetic ECM prior to implantation, vascular functionalization of ECM structures to enhance angiogenesis after implantation, generation of engineered animals as human organ donors, and embryonic and pluripotent stem cell-derived endocrine cells that may be encapsulated or genetically engineered to be immunotolerated. Substantial technological improvements have been made to regenerate or engineer endocrine pancreatic tissue; however, significant hurdles remain, and more research is needed to develop a technology to integrate all components of viable endocrine tissue for clinical application.
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Affiliation(s)
- Antonio Citro
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Harald C Ott
- Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 4700, Boston, MA, 02114, USA.
- Harvard Medical School, Boston, MA, USA.
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
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40
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Abstract
PURPOSES OF REVIEW Scattered throughout the pancreas, the endocrine islets rely on neurovascular support for signal relay to regulate hormone secretion and for maintaining tissue homeostasis. The islet accessory cells (or components) of neurovascular tissues include the endothelial cells, pericytes, smooth muscle cells, neurons (nerve fibers), and glia. Research results derived from experimental diabetes and islet transplantation indicate that the accessory cells are reactive in islet injury and can affect islet function and homeostasis in situ or in an ectopic environment. RECENT FINDINGS Recent advances in cell labeling and tissue imaging have enabled investigation of islet accessory cells to gain insights into their network structures, functions, and remodeling in disease. It has become clear that in diabetes, the islet neurovascular tissues are not just bystanders damaged in neuropathy and vascular complications; rather, they participate in islet remodeling in response to changes in the microenvironment. Because of the fundamental differences between humans and animal models in neuroinsular cytoarchitecture and cell proliferation, examination of islet accessory cells in clinical specimens and donor pancreases warrants further attention.
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Affiliation(s)
- Shiue-Cheng Tang
- Department of Medical Science and Institute of Biotechnology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Claire F Jessup
- College of Medicine and Public Health, Flinders University and Discipline of Medicine, University of Adelaide, Adelaide, SA, 5001, Australia.
| | - Martha Campbell-Thompson
- Department of Pathology, Immunology, and Laboratory Medicine, 1395 Center Drive, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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42
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Staels W, Verdonck Y, Heremans Y, Leuckx G, De Groef S, Heirman C, de Koning E, Gysemans C, Thielemans K, Baeyens L, Heimberg H, De Leu N. Vegf-A mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation. Diabetologia 2018; 61:1804-1810. [PMID: 29789879 DOI: 10.1007/s00125-018-4646-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 04/23/2018] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment. METHODS Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice. RESULTS At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean ± SEM: 0.118 ± 0.01 [n = 3] in Vegf-A mRNA transfected group (VEGF) vs 0.056 ± 0.01 [n = 3] in no RNA [p < 0.05] vs 0.063 ± 0.02 [n = 4] in Gfp mRNA transfected group (GFP) [p < 0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085 ± 0.02 [n = 4] in VEGF vs 0.030 ± 0.004 [n = 4] in no RNA [p < 0.05] vs 0.034 ± 0.01 [n = 5] in GFP [p < 0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048 ± 0.013 [n = 3] in VEGF vs 0.015 ± 0.0051 [n = 4] in no RNA [p < 0.01] vs 0.013 ± 0.0046 [n = 4] in GFP [p < 0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049 ± 0.0042 [n = 8] in VEGF vs 0.029 ± 0.0052 [n = 5] in no RNA [p < 0.05] vs 0.027 ± 0.0056 [n = 4] in GFP [p < 0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292 ± 0.0032 μl [n = 7] in VEGF vs 0.0178 ± 0.0021 μl [n = 5] in no RNA [p < 0.01] vs 0.0129 ± 0.0012 μl [n = 4] in GFP [p < 0.001]). CONCLUSIONS/INTERPRETATION Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.
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Affiliation(s)
- Willem Staels
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Department of Paediatrics, Division of Paediatric Endocrinology, Ghent University, Ghent, Belgium
| | - Yannick Verdonck
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Gunter Leuckx
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Sofie De Groef
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Carlo Heirman
- Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Eelco de Koning
- Department of Medicine, Section of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
| | - Conny Gysemans
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Kris Thielemans
- Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Luc Baeyens
- 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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Lebreton F, Berishvili E, Parnaud G, Rouget C, Bosco D, Berney T, Lavallard V. NLRP3 inflammasome is expressed and regulated in human islets. Cell Death Dis 2018; 9:726. [PMID: 29941940 PMCID: PMC6018156 DOI: 10.1038/s41419-018-0764-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 06/05/2018] [Accepted: 06/08/2018] [Indexed: 02/02/2023]
Abstract
NRLP3 inflammasome is a protein complex involved in the maturation of IL1β. In the onset of type 1 diabetes as well as in islet transplantation, IL-1β is one of the cytokines involved in the recruitment of immune cells in islets and eventually in islet destruction. Whether IL-1β is produced by islet cells is still under debate and NLRP3 inflammasome-dependent IL-1β production has not been yet determined in human islets. The aim of this study was to determine the expression and the regulation of the NRLP3 inflammasome in human islets. Human islets were stimulated with LPS and successively with ATP (LPS + ATP) in the presence or absence of the inflammasome inhibitor glyburide. Islets were also incubated in hypoxic or normoxic conditions for 24 h in the presence or absence of glyburide. Then, IL1B and NLRP3 expression was studied by real time PCR, protein expression by western blot, protein localization by immunofluorescence and protein secretion by ELISA. LPS + ATP increased gene expression of NRLP3 and IL1B. Glyburide partially prevented this effect. IL-1β protein was localized in β and non-β cells. Moreover, LPS + ATP increased IL-1β protein expression and production, which were prevented by glyburide. Hypoxia increased gene expression of NRLP3 and IL1B and induced IL-1β and caspase-1 production. Finally, hypoxia-induced cell death which was not prevented by inhibition of NLRP3 inflammasome. NRLP3 inflammasome is expressed and plays a role in IL-1β production by human islets. By contrast, NRLP3 inflammasome activation is not involved in islet cell death induced by hypoxia.
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Affiliation(s)
- Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University, Hospitals and University of Geneva, Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University, Hospitals and University of Geneva, Geneva, Switzerland
| | - Géraldine Parnaud
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University, Hospitals and University of Geneva, Geneva, Switzerland
| | - Caroline Rouget
- 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
| | - Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University, Hospitals and University of Geneva, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University, Hospitals and University of Geneva, Geneva, Switzerland.
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44
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Nie W, Ma X, Yang C, Chen Z, Rong P, Wu M, Jiang J, Tan M, Yi S, Wang W. Human mesenchymal-stem-cells-derived exosomes are important in enhancing porcine islet resistance to hypoxia. Xenotransplantation 2018; 25:e12405. [PMID: 29932262 DOI: 10.1111/xen.12405] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/25/2018] [Accepted: 04/16/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hypoxia-induced damage is one of the key factors associated with islet graft dysfunction. Mesenchymal stem cells (MSCs) could be used to enhance the therapeutic effect of islet transplantation due to their paracrine potential such as exosomes. In this study, we investigated whether exosomes from human umbilical cord-derived MSC-conditioned medium (hu-MSC-CM) could increase the survival and function of neonatal porcine islet cell clusters (NICCs) exposed to hypoxia. METHODS Neonatal porcine islet cell clusters were cultured with hu-MSC-CM, with or without exosomes, and native medium RPMI-1640 (Control) under hypoxic conditions (1% O2 ). The effects of exosomes on NICCs viability and function in vitro were examined by FACS, the Loops system, and the Extracellular Flux assay, respectively. RESULTS Compared with NICCs cultured in RPMI-1640 medium and hu-MSC-CM without exosomes, the survival ratio, viability, and function increased in NICCs cultured in hu-MSC-CM with exosomes. CONCLUSIONS This study found that hu-MSC-CM could protect NICCs from hypoxia-induced dysfunction, and exosomes played an important role in hypoxic resistance, suggesting a potential strategy to improve islet transplantation outcomes.
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Affiliation(s)
- Wei Nie
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Xiaoqian Ma
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Cejun Yang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Zeyi Chen
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Pengfei Rong
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Jianhui Jiang
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Mengqun Tan
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Shounan Yi
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China.,Center for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
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45
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Katabathina VS, Rikhtehgar OY, Dasyam AK, Manickam R, Prasad SR. Genetics of Pancreatic Neoplasms and Role of Screening. Magn Reson Imaging Clin N Am 2018; 26:375-389. [PMID: 30376976 DOI: 10.1016/j.mric.2018.03.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
There is a wide spectrum of pancreatic neoplasms with characteristic genetic abnormalities, tumor pathways, and histopathology that primarily determine tumor biology, treatment response, and prognosis. Although most pancreatic tumors are sporadic, 10% of neoplasms occur in the setting of distinct hereditary syndromes. Detailed studies of these rare syndromes have allowed researchers to identify a myriad of specific genetic signatures of pancreatic tumors. A better understanding of tumor genomics may have significant clinical implications in the diagnosis and management of patients with pancreatic tumors. Evolving knowledge has paved the way to screening paradigms and protocols in individuals at higher risk of developing pancreatic tumors.
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Affiliation(s)
- Venkata S Katabathina
- Department of Radiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Omid Y Rikhtehgar
- Department of Radiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Anil K Dasyam
- Department of Radiology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Rohan Manickam
- Department of Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler street, Unit 1473, Houston, TX 77030, USA
| | - Srinivasa R Prasad
- Department of Radiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler street, Unit 1473, Houston, TX 77030, USA.
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46
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Fujita I, Utoh R, Yamamoto M, Okano T, Yamato M. The liver surface as a favorable site for islet cell sheet transplantation in type 1 diabetes model mice. Regen Ther 2018; 8:65-72. [PMID: 30271868 PMCID: PMC6147207 DOI: 10.1016/j.reth.2018.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/19/2018] [Accepted: 04/12/2018] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Islet transplantation is one of the most promising therapeutic approaches for patients with severe type 1 diabetes mellitus (T1DM). Transplantation of engineered islet cell sheets holds great potential for treating T1DM as it enables the creation of stable neo-islet tissues. However, a large mass of islet cell sheets is required for the subcutaneous transplantation to reverse hyperglycemia in diabetic mice. Here, we investigated whether the liver surface could serve as an alternative site for islet cell sheet transplantation. METHODS Dispersed rat islet cells (0.8 × 106 cells) were cultured on laminin-332-coated thermoresponsive culture dishes. After 2 days of cultivation, we harvested the islet cell sheets by lowering the culture temperature using a support membrane with a gelatin gel. We transplanted two recovered islet cell sheets into the subcutaneous space or onto the liver surface of severe combined immunodeficiency (SCID) mice with streptozocin-induced diabetes. RESULTS In the liver surface group, the non-fasting blood glucose level decreased rapidly within several days after transplantation. In marked contrast, the hyperglycemia state was maintained in the subcutaneous space transplantation group. The levels of rat C-peptide and insulin in the liver surface group were significantly higher than those in the subcutaneous space group. An immunohistological analysis confirmed that most of the islet cells engrafted on the liver surface were insulin-positive. The CD31-positive endothelial cells formed vascular networks within the neo-islets and in the surrounding tissues. In contrast, viable islet cells were not found in the subcutaneous space group. CONCLUSIONS Compared with the subcutaneous space, a relatively small mass of islet cell sheets was enough to achieve normoglycemia in diabetic mice when the liver surface was selected as the transplantation site. Our results demonstrate that the optimization of the transplantation site for islet cell sheets leads to significant improvements in the therapeutic efficiency for T1DM.
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Affiliation(s)
- Izumi Fujita
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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47
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Ji R, Li J, Yin Z, Liu Y, Cang L, Wang M, Shi Y. Pancreatic stiffness response to an oral glucose load in obese adults measured by magnetic resonance elastography. Magn Reson Imaging 2018; 51:113-119. [PMID: 29729951 DOI: 10.1016/j.mri.2018.04.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 04/30/2018] [Accepted: 04/30/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND To test the feasibility of magnetic resonance elastography (MRE) for assessing changes in pancreatic stiffness of obese adults administered an oral glucose load. METHODS MRE scans were performed on 21 asymptomatic obese volunteers (BMI ≥ 27 kg/m2) before and after receiving a 75-g oral glucose load, and repeated in 7 days without a glucose load. Shear waves at 40 and 60 Hz were introduced into the upper abdomen by a pneumatic drum driver (diameter of 12 cm). Two radiologists subjectively graded the overall quality of the wave images of the pancreas using a scale from 1 to 4, in which suboptimal image quality was considered to be scores of 1 and 2. RESULTS Good inter-observer agreement was found for image quality at both frequencies (kappa = 0.805 for 40 Hz and 0.762 for 60 Hz). The median overall image quality score was significantly higher in 40 Hz than that of 60 Hz (4 versus 2). At 40 Hz, pancreatic stiffness in response to oral glucose had a decrease of 6.7% (pre vs post: 1.17 ± 0.13 kPa vs 1.08 ± 0.12 kPa; P < 0.001), whereas the change in stiffness was not significant at 60 Hz (pre vs post: 2.01 ± 0.21 kPa vs 2.02 ± 0.24 kPa; P = 0.695). Excellent intersession agreement was found for MRE acquisitions at 40 Hz with an overall intraclass correlation coefficient = 0.947 (95% confidence interval: 0.913-0.967). CONCLUSION MRE at 40 Hz provides good-quality wave images and high sensitivity to changes in the mechanical properties of pancreatic tissue in obese volunteers after an oral glucose load.
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Affiliation(s)
- Ruoyun Ji
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jiahui Li
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ziying Yin
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Yanqing Liu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lizhuo Cang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Min Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Shi
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China.
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Gao X, Lindqvist A, Sandberg M, Groop L, Wierup N, Jansson L. Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats. Physiol Rep 2018; 6:e13685. [PMID: 29673130 PMCID: PMC5907939 DOI: 10.14814/phy2.13685] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 03/13/2018] [Accepted: 03/15/2018] [Indexed: 12/22/2022] Open
Abstract
The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion, and affects β-cell turnover. This study aimed at evaluating if some of the beneficial effects of GIP on glucose homeostasis can be explained by modulation of islet blood flow. Anesthetized Sprague-Dawley rats were infused intravenously with different doses of GIP (10, 20, or 60 ng/kg*min) for 30 min. Subsequent organ blood flow measurements were performed with microspheres. In separate animals, islets were perfused ex vivo with GIP (10-6 -10-12 mol/L) during normo- and hyperglycemia and arteriolar responsiveness was recorded. The highest dose of GIP potentiated insulin secretion during hyperglycemia, but had no effect in normoglycemic rats. The highest GIP concentration decreased blood perfusion of whole pancreas, pancreatic islets, duodenum, colon, liver and kidneys. The decrease in blood flow was unaffected by ganglion blockade or adenosine receptor inhibition. In contrast to this, in single perfused islets GIP induced a dose-dependent arteriolar dilation. Thus, high doses of GIP exert a direct dilatory effect on islet arterioles in isolated islets, but induce a generalized vasoconstriction in splanchnic organs, including the whole pancreas and islets, in vivo. The latter effect is unlikely to be mediated by adenosine, the autonomic nervous system, or endothelial mediators.
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Affiliation(s)
- Xiang Gao
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Andreas Lindqvist
- Department of Clinical SciencesLund University Diabetes CentreLund UniversityMalmöSweden
| | - Monica Sandberg
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Leif Groop
- Department of Clinical SciencesLund University Diabetes CentreLund UniversityMalmöSweden
| | - Nils Wierup
- Department of Clinical SciencesLund University Diabetes CentreLund UniversityMalmöSweden
| | - Leif Jansson
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
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Boss C, Bouche N, De Marchi U. Encapsulated Optically Responsive Cell Systems: Toward Smart Implants in Biomedicine. Adv Healthc Mater 2018; 7:e1701148. [PMID: 29283209 DOI: 10.1002/adhm.201701148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 11/06/2017] [Indexed: 01/09/2023]
Abstract
Managing increasingly prevalent chronic diseases will require close continuous monitoring of patients. Cell-based biosensors may be used for implantable diagnostic systems to monitor health status. Cells are indeed natural sensors in the body. Functional cellular systems can be maintained in the body for long-term implantation using cell encapsulation technology. By taking advantage of recent progress in miniaturized optoelectronic systems, the genetic engineering of optically responsive cells may be combined with cell encapsulation to generate smart implantable cell-based sensing systems. In biomedical research, cell-based biosensors may be used to study cell signaling, therapeutic effects, and dosing of bioactive molecules in preclinical models. Today, a wide variety of genetically encoded fluorescent sensors have been developed for real-time imaging of living cells. Here, recent developments in genetically encoded sensors, cell encapsulation, and ultrasmall optical systems are highlighted. The integration of these components in a new generation of biosensors is creating innovative smart in vivo cell-based systems, bringing novel perspectives for biomedical research and ultimately allowing unique health monitoring applications.
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Affiliation(s)
- Christophe Boss
- Device EngineeringNestlé Institute of Health Sciences EPFL Innovation Park Lausanne CH‐1015 Switzerland
| | - Nicolas Bouche
- Device EngineeringNestlé Institute of Health Sciences EPFL Innovation Park Lausanne CH‐1015 Switzerland
| | - Umberto De Marchi
- Mitochondrial FunctionNestlé Institute of Health Sciences EPFL Innovation Park Lausanne CH‐1015 Switzerland
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50
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Wang Z, Peng L, Song YL, Xu S, Hua Z, Fang N, Zhai M, Liu H, Fang Q, Deng T, Zhang W, Chen YJ, Lou J. Pseudo-hemorrhagic region formation in pancreatic neuroendocrine tumors is a result of blood vessel dilation followed by endothelial cell detachment. Oncol Lett 2018. [PMID: 29541192 PMCID: PMC5835859 DOI: 10.3892/ol.2018.7840] [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] [Indexed: 01/09/2023] Open
Abstract
Aberrant blood vessel formation and hemorrhage may contribute to tumor progression and are potential targets in the treatment of several types of cancer. Pancreatic neuroendocrine tumors (PNETs) are highly vascularized, particularly when they are well-differentiated. However, the process of vascularization and endothelial cell detachment in PNETs is poorly understood. In the present study, 132 PNET clinical samples were examined and a special type of hemorrhagic region was observed in ~30% of the samples regardless of tumor subtype. These hemorrhagic regions were presented as blood-filled caverns with a smooth boundary and were unlined by endothelial cells. Based on the extensive endothelial cell detachment observed in the clinical samples, the formation process of these blood-filled caverns was hypothesized. Blood vessel dilation followed by detachment of endothelial cells from the surrounding tumor tissue was speculated. This was further supported using an INS-1 xenograft insulinoma model. As the formation process was distinct from the typical diffusive hemorrhage, it was named ‘pseudo-hemorrhage’. Furthermore, it was demonstrated that epithelial (E-) cadherin and β-catenin were overexpressed in tumor cells surrounding these pseudo-hemorrhagic regions. Therefore, even though no statistically significant association of pseudo-hemorrhage with clinical features (metastasis or disease recurrence) was identified, the high levels of E-cadherin and β-catenin expression may suggest that a number of features of normal islet cells are retained.
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Affiliation(s)
- Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Yu-Li Song
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Shiqing Xu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Zhan Hua
- Department of General Surgery, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Ni Fang
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Min Zhai
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Honglin Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Qing Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Tingting Deng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Wenjian Zhang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
| | - Yuan-Jia Chen
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China
| | - Jinning Lou
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chaoyang, Beijing 100029, P.R. China
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