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Gabriel Silvério Scholl V, Todeschini Justus L, Girotto OS, Karine Pasqual K, Garcia MHH, da Silva Petronio FG, de Moraes AF, Maria Barbalho S, Araújo AC, Fornari Laurindo L, Camargo CP, Miglino MA. Assessing Implantation Sites for Pancreatic Islet Cell Transplantation: Implications for Type 1 Diabetes Mellitus Treatment. Bioengineering (Basel) 2025; 12:499. [PMID: 40428118 DOI: 10.3390/bioengineering12050499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Type 1 diabetes mellitus (T1DM) involves the destruction of pancreatic β-cells, requiring ongoing insulin therapy. A promising alternative for management is pancreatic islet transplantation, or the bioartificial pancreas. Here, we examine the primary implantation sites for the bioartificial pancreas, highlighting their anatomical, physical, and immunological characteristics in the context of T1DM treatment. Traditionally used for islet transplantation, the liver promotes metabolic efficiency due to portal drainage; however, it presents issues such as hypoxia and inflammatory responses. The omentum offers excellent vascularization but has limited capacity for subsequent transplants. The renal subcapsular space is advantageous when combined with kidney transplants; however, its use is limited due to low vascularization. The subcutaneous space is notable for its accessibility and lower invasiveness, although its poor vascularization poses significant challenges. These challenges can be mitigated with bioengineering strategies. The gastrointestinal submucosa provides easy access and good vascularization, which makes it a promising option for endoscopic approaches. Additionally, the intrapleural space, which remains underexplored, offers benefits such as increased oxygenation and reduced inflammatory response. Selecting the ideal site for bioartificial pancreas implantation should balance graft support, complication reduction, and surgical accessibility. Bioengineered devices and scaffolds can address the limitations of traditional sites and enhance T1DM management.
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Affiliation(s)
- Vinícius Gabriel Silvério Scholl
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Leonardo Todeschini Justus
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Otávio Simões Girotto
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Kelly Karine Pasqual
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Matheus Henrique Herminio Garcia
- Postgraduate Program in Animal Health, Production and Environment, School of Veterinary Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | | | - Aline Flores de Moraes
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília 17500-000, SP, Brazil
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Cristina Pires Camargo
- Microsurgery and Plastic Surgery Laboratory (LIM-04), Faculdade de Medicina, Universidade de São Paulo, São Paulo 05508-220, SP, Brazil
| | - Maria Angélica Miglino
- Postgraduate Program in Animal Health, Production and Environment, School of Veterinary Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Department of Animal Anatomy, School of Veterinary Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
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2
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Masset C, Drillaud N, Ternisien C, Degauque N, Gerard N, Bruneau S, Branchereau J, Blancho G, Mesnard B, Brouard S, Giral M, Cantarovich D, Dantal J. The concept of immunothrombosis in pancreas transplantation. Am J Transplant 2025; 25:650-668. [PMID: 39709128 DOI: 10.1016/j.ajt.2024.11.025] [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: 08/09/2024] [Revised: 11/06/2024] [Accepted: 11/23/2024] [Indexed: 12/23/2024]
Abstract
Early failure of a pancreatic allograft due to complete thrombosis has an incidence of approximately 10% and is the main cause of comorbidity in pancreas transplantation. Although several risk factors have been identified, the exact mechanisms leading to this serious complication are still unclear. In this review, we define the roles of the individual components involved during sterile immunothrombosis-namely endothelial cells, platelets, and innate immune cells. Further, we review the published evidence linking the main risk factors for pancreatic thrombosis to cellular activation and vascular modifications. We also explore the unique features of the pancreas itself: the vessel endothelium, specific vascularization, and relationship to other organs-notably the spleen and adipose tissue. Finally, we summarize the therapeutic possibilities for the prevention of pancreatic thrombosis depending on the different mechanisms such as anticoagulation, anti-inflammatory molecules, endothelium protectors, antagonism of damage-associated molecular patterns, and use of machine perfusion.
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Affiliation(s)
- Christophe Masset
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France.
| | - Nicolas Drillaud
- Laboratory of Hemostasis, Nantes University Hospital, Nantes, France
| | | | - Nicolas Degauque
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Nathalie Gerard
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Sarah Bruneau
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Julien Branchereau
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Gilles Blancho
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Benoit Mesnard
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Sophie Brouard
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Magali Giral
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Diego Cantarovich
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
| | - Jacques Dantal
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France; Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France
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Wong JM, Pepper AR. Status of islet transplantation and innovations to sustainable outcomes: novel sites, cell sources, and drug delivery strategies. FRONTIERS IN TRANSPLANTATION 2024; 3:1485444. [PMID: 39553396 PMCID: PMC11565603 DOI: 10.3389/frtra.2024.1485444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/21/2024] [Indexed: 11/19/2024]
Abstract
Islet transplantation (ITx) is an effective means to restore physiologic glycemic regulation in those living with type 1 diabetes; however, there are a handful of barriers that prevent the broad application of this functionally curative procedure. The restricted cell supply, requisite for life-long toxic immunosuppression, and significant immediate and gradual graft attrition limits the procedure to only those living with brittle diabetes. While intraportal ITx is the primary clinical site, portal vein-specific factors including low oxygen tension and the instant blood-mediated inflammatory reaction are detrimental to initial engraftment and long-term function. These factors among others prevent the procedure from granting recipients long-term insulin independence. Herein, we provide an overview of the status and limitations of ITx, and novel innovations that address the shortcomings presented. Despite the marked progress highlighted in the review from as early as the initial islet tissue transplantation in 1893, ongoing efforts to improve the procedure efficacy and success are also explored. Progress in identifying unlimited cell sources, more favourable transplant sites, and novel drug delivery strategies all work to broaden ITx application and reduce adverse outcomes. Exploring combination of these approaches may uncover synergies that can further advance the field of ITx in providing sustainable functional cures. Finally, the potential of biomaterial strategies to facilitate immune evasion and local immune modulation are featured and may underpin successful application in alternative transplant sites.
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Affiliation(s)
| | - Andrew R. Pepper
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Yue L, Li J, Yao M, Song S, Zhang X, Wang Y. Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation. Front Immunol 2024; 15:1455691. [PMID: 39346923 PMCID: PMC11427288 DOI: 10.3389/fimmu.2024.1455691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.
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Affiliation(s)
- Liting Yue
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingjun Yao
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Xiaoqin Zhang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Chengdu, China
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Tedla MG, Wright N, Yolcu ES, Wang Y, Shirwan H. Protocol for transplanting pancreatic islets into the parametrial fat pad of female mice. STAR Protoc 2024; 5:102816. [PMID: 38180833 PMCID: PMC10801339 DOI: 10.1016/j.xpro.2023.102816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/13/2023] [Accepted: 12/18/2023] [Indexed: 01/07/2024] Open
Abstract
Although the male epididymal fat pad is an effective site for islet transplantation, females lack this tissue. Here, we present a protocol to assess the parametrial fat pad (PFP) adjacent to the uterine horn in females as an alternative site for islet transplantation. We describe steps for islet isolation from the pancreas, counting, transplantation into PFP, and monitoring for engraftment. Transplantation into PFP is minimally invasive, time efficient, and supports long-term engraftment of syngeneic islets and rejection of allogeneic islets. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2022).1.
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Affiliation(s)
- Mebrahtu G Tedla
- Department of Pediatrics, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA; Department of Molecular Microbiology and Immunology, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA; NextGen Precision Health Institute, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA
| | - Nathaniel Wright
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Esma S Yolcu
- Department of Pediatrics, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA; Department of Molecular Microbiology and Immunology, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA; NextGen Precision Health Institute, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA
| | - Yadong Wang
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Haval Shirwan
- Department of Pediatrics, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO 65211, USA.
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Abbas N, You K, Getachew A, Wu F, Hussain M, Huang X, Chen Y, Pan T, Li Y. Kupffer cells abrogate homing and repopulation of allogeneic hepatic progenitors in injured liver site. Stem Cell Res Ther 2024; 15:48. [PMID: 38378583 PMCID: PMC10877762 DOI: 10.1186/s13287-024-03656-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/05/2024] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND Allogeneic hepatocyte transplantation is an emerging approach to treat acute liver defects. However, durable engraftment of the transplanted cells remains a daunting task, as they are actively cleared by the recipient's immune system. Therefore, a detailed understanding of the innate or adaptive immune cells-derived responses against allogeneic transplanted hepatic cells is the key to rationalize cell-based therapies. METHODS Here, we induced an acute inflammatory regenerative niche (3-96 h) on the surface of the liver by the application of cryo-injury (CI) to systematically evaluate the innate immune response against transplanted allogeneic hepatic progenitors in a sustained micro-inflammatory environment. RESULTS The resulting data highlighted that the injured site was significantly repopulated by alternating numbers of innate immune cells, including neutrophils, monocytes and Kupffer cells (KCs), from 3 to 96 h. The transplanted allo-HPs, engrafted 6 h post-injury, were collectively eliminated by the innate immune response within 24 h of transplantation. Selective depletion of the KCs demonstrated a delayed recruitment of monocytes from day 2 to day 6. In addition, the intrasplenic engraftment of the hepatic progenitors 54 h post-transplantation was dismantled by KCs, while a time-dependent better survival and translocation of the transplanted cells into the injured site could be observed in samples devoid of KCs. CONCLUSION Overall, this study provides evidence that KCs ablation enables a better survival and integration of allo-HPs in a sustained liver inflammatory environment, having implications for rationalizing the cell-based therapeutic interventions against liver defects.
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Affiliation(s)
- Nasir Abbas
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Centre for Regenerative Medicine and Health (CRMH), Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Hong Kong, Hong Kong SAR, China
| | - Kai You
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Anteneh Getachew
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, USA
| | - Feima Wu
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Muzammal Hussain
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Xinping Huang
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Yan Chen
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Tingcai Pan
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong Province, China
| | - Yinxiong Li
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
- State Key Laboratory of Respiratory Disease, Guangzhou, 510000, China.
- China-New Zealand Joint Laboratory of Biomedicine and Health, Guangzhou, 510530, China.
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Turan A, Zhang L, Tarique M, Ulker V, Arguc FN, Badal D, Yolcu ES, Shirwan H. Engineering pancreatic islets with a novel form of thrombomodulin protein to overcome early graft loss triggered by instant blood-mediated inflammatory reaction. Am J Transplant 2023; 23:619-628. [PMID: 36863480 PMCID: PMC10318623 DOI: 10.1016/j.ajt.2023.02.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 02/23/2023] [Indexed: 03/04/2023]
Abstract
The instant blood-mediated inflammatory reaction (IBMIR) is initiated by innate immune responses that cause substantial islet loss after intraportal transplantation. Thrombomodulin (TM) is a multifaceted innate immune modulator. In this study, we report the generation of a chimeric form of thrombomodulin with streptavidin (SA-TM) for transient display on the surface of islets modified with biotin to mitigate IBMIR. SA-TM protein expressed in insect cells showed the expected structural and functional features. SA-TM converted protein C into activated protein C, blocked phagocytosis of xenogeneic cells by mouse macrophages and inhibited neutrophil activation. SA-TM was effectively displayed on the surface of biotinylated islets without a negative effect on their viability or function. Islets engineered with SA-TM showed improved engraftment and established euglycemia in 83% of diabetic recipients when compared with 29% of recipients transplanted with SA-engineered islets as control in a syngeneic minimal mass intraportal transplantation model. Enhanced engraftment and function of SA-TM-engineered islets were associated with the inhibition of intragraft proinflammatory innate cellular and soluble mediators of IBMIR, such as macrophages, neutrophils, high-mobility group box 1, tissue factor, macrophage chemoattractant protein-1, interleukin-1β, interleukin-6, tumor necrosis factor-α, interferon-γ. Transient display of SA-TM protein on the islet surface to modulate innate immune responses causing islet graft destruction has clinical potential for autologous and allogeneic islet transplantation.
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Affiliation(s)
- Ali Turan
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA
| | - Lei Zhang
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA
| | - Mohammad Tarique
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA
| | - Vahap Ulker
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA
| | - Feyza Nur Arguc
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA
| | - Darshan Badal
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA
| | - Esma S Yolcu
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA.
| | - Haval Shirwan
- Department of Child Health,University of Missouri,Columbia,Missouri,USA; Department of Molecular Microbiology and Immunology,University of Missouri,Columbia,Missouri,USA; NextGen Precision Health,University of Missouri,Columbia,Missouri,USA.
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8
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Naqvi RA, Naqvi AR, Singh A, Priyadarshini M, Balamurugan AN, Layden BT. The future treatment for type 1 diabetes: Pig islet- or stem cell-derived β cells? Front Endocrinol (Lausanne) 2023; 13:1001041. [PMID: 36686451 PMCID: PMC9849241 DOI: 10.3389/fendo.2022.1001041] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/07/2022] [Indexed: 01/06/2023] Open
Abstract
Replacement of β cells is only a curative approach for type 1 diabetes (T1D) patients to avoid the threat of iatrogenic hypoglycemia. In this pursuit, islet allotransplantation under Edmonton's protocol emerged as a medical miracle to attain hypoglycemia-free insulin independence in T1D. Shortage of allo-islet donors and post-transplantation (post-tx) islet loss are still unmet hurdles for the widespread application of this therapeutic regimen. The long-term survival and effective insulin independence in preclinical studies have strongly suggested pig islets to cure overt hyperglycemia. Importantly, CRISPR-Cas9 technology is pursuing to develop "humanized" pig islets that could overcome the lifelong immunosuppression drug regimen. Lately, induced pluripotent stem cell (iPSC)-derived β cell approaches are also gaining momentum and may hold promise to yield a significant supply of insulin-producing cells. Theoretically, personalized β cells derived from a patient's iPSCs is one exciting approach, but β cell-specific immunity in T1D recipients would still be a challenge. In this context, encapsulation studies on both pig islet as well as iPSC-β cells were found promising and rendered long-term survival in mice. Oxygen tension and blood vessel growth within the capsules are a few of the hurdles that need to be addressed. In conclusion, challenges associated with both procedures, xenotransplantation (of pig-derived islets) and stem cell transplantation, are required to be cautiously resolved before their clinical application.
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Affiliation(s)
- Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Afsar Raza Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States
| | - Amar Singh
- Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Medha Priyadarshini
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Appakalai N. Balamurugan
- Center for Clinical and Translational Research, Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Brian T. Layden
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
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9
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Sykes M, Sachs DH. Progress in xenotransplantation: overcoming immune barriers. Nat Rev Nephrol 2022; 18:745-761. [PMID: 36198911 DOI: 10.1038/s41581-022-00624-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2022] [Indexed: 11/09/2022]
Abstract
A major limitation of organ allotransplantation is the insufficient supply of donor organs. Consequently, thousands of patients die every year while waiting for a transplant. Progress in xenotransplantation that has permitted pig organ graft survivals of years in non-human primates has led to renewed excitement about the potential of this approach to alleviate the organ shortage. In 2022, the first pig-to-human heart transplant was performed on a compassionate use basis, and xenotransplantation experiments using pig kidneys in deceased human recipients provided encouraging data. Many advances in xenotransplantation have resulted from improvements in the ability to genetically modify pigs using CRISPR-Cas9 and other methodologies. Gene editing has the capacity to generate pig organs that more closely resemble those of humans and are hence more physiologically compatible and less prone to rejection. Despite such modifications, immune responses to xenografts remain powerful and multi-faceted, involving innate immune components that do not attack allografts. Thus, the induction of innate and adaptive immune tolerance to prevent rejection while preserving the capacity of the immune system to protect the recipient and the graft from infection is desirable to enable clinical xenotransplantation.
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Affiliation(s)
- Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, USA. .,Department of Surgery, Columbia University, New York, NY, USA. .,Department of Microbiology and Immunology, Columbia University, New York, NY, USA.
| | - David H Sachs
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, USA. .,Department of Surgery, Columbia University, New York, NY, USA.
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10
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Jeyagaran A, Lu CE, Zbinden A, Birkenfeld AL, Brucker SY, Layland SL. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev 2022; 189:114481. [PMID: 36002043 PMCID: PMC9531713 DOI: 10.1016/j.addr.2022.114481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 01/24/2023]
Abstract
The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
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Affiliation(s)
- Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University Tübingen, 72770 Reutlingen, Germany
| | - Chuan-En Lu
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Aline Zbinden
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Munich, Germany
| | - Sara Y Brucker
- Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.
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11
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Hu M, Hawthorne WJ, Yi S, O’Connell PJ. Cellular Immune Responses in Islet Xenograft Rejection. Front Immunol 2022; 13:893985. [PMID: 35874735 PMCID: PMC9300897 DOI: 10.3389/fimmu.2022.893985] [Citation(s) in RCA: 6] [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: 03/11/2022] [Accepted: 06/08/2022] [Indexed: 11/18/2022] Open
Abstract
Porcine islets surviving the acute injury caused by humoral rejection and IBMIR will be subjected to cellular xenograft rejection, which is predominately mediated by CD4+ T cells and is characterised by significant infiltration of macrophages, B cells and T cells (CD4+ and CD8+). Overall, the response is different compared to the alloimmune response and more difficult to suppress. Activation of CD4+ T cells is both by direct and indirect antigen presentation. After activation they recruit macrophages and direct B cell responses. Although they are less important than CD4+ T cells in islet xenograft rejection, macrophages are believed to be a major effector cell in this response. Rodent studies have shown that xenoantigen-primed and CD4+ T cell-activated macrophages were capable of recognition and rejection of pancreatic islet xenografts, and they destroyed a graft via the secretion of various proinflammatory mediators, including TNF-α, reactive oxygen and nitrogen species, and complement factors. B cells are an important mediator of islet xenograft rejection via xenoantigen presentation, priming effector T cells and producing xenospecific antibodies. Depletion and/or inhibition of B cells combined with suppressing T cells has been suggested as a promising strategy for induction of xeno-donor-specific T- and B-cell tolerance in islet xenotransplantation. Thus, strategies that expand the influence of regulatory T cells and inhibit and/or reduce macrophage and B cell responses are required for use in combination with clinical applicable immunosuppressive agents to achieve effective suppression of the T cell-initiated xenograft response.
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Affiliation(s)
- Min Hu
- Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Wayne J. Hawthorne
- Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Shounan Yi
- Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Philip J. O’Connell
- Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- *Correspondence: Philip J. O’Connell,
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12
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Bergman ZR, Robbins AJ, Alwan FS, Bellin MD, Kirchner VA, Pruett TL, Mulier KE, Boucher AA, Lusczek ER, Beilman GJ. Perioperative Coagulation Changes in Total Pancreatectomy and Islet Autotransplantation. Pancreas 2022; 51:671-677. [PMID: 36099513 PMCID: PMC9547836 DOI: 10.1097/mpa.0000000000002085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure. METHODS This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals. RESULTS Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation. CONCLUSIONS Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.
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Affiliation(s)
| | | | | | | | | | | | | | - Alex A Boucher
- Pediatric Hematology and Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MN
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13
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Walker S, Appari M, Forbes S. Considerations and challenges of islet transplantation and future therapies on the horizon. Am J Physiol Endocrinol Metab 2022; 322:E109-E117. [PMID: 34927459 DOI: 10.1152/ajpendo.00310.2021] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulin-producing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes.
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Affiliation(s)
- Sophie Walker
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Mahesh Appari
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Shareen Forbes
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
- Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
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14
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Boucher AA, Wastvedt S, Hodges JS, Beilman GJ, Kirchner VA, Pruett TL, Hering BJ, Schwarzenberg SJ, Downs E, Freeman M, Trikudanathan G, Chinnakotla S, Bellin MD. Portal Vein Thrombosis May Be More Strongly Associated With Islet Infusion Than Extreme Thrombocytosis After Total Pancreatectomy With Islet Autotransplantation. Transplantation 2021; 105:2499-2506. [PMID: 33988346 DOI: 10.1097/tp.0000000000003624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Total pancreatectomy with islet autotransplantation (TPIAT) involves pancreatectomy, splenectomy, and reinjection of the patient's pancreatic islets into the portal vein. This process triggers a local inflammatory reaction and increase in portal pressure, threatening islet survival and potentially causing portal vein thrombosis. Recent research has highlighted a high frequency of extreme thrombocytosis (platelets ≥1000 × 109/L) after TPIAT, but its cause and association with thrombotic risk remain unclear. METHODS This retrospective single-site study of a contemporary cohort of 409 pediatric and adult patients analyzed the frequency of thrombocytosis, risk factors for thrombosis, and antiplatelet and anticoagulation strategies. RESULTS Of 409 patients, 67% developed extreme thrombocytosis, peaking around postoperative day 16. Extreme thrombocytosis was significantly associated with infused islet volumes. Thromboembolic events occurred in 12.2% of patients, with portal vein thromboses occurring significantly earlier than peripheral thromboses. Portal vein thromboses were associated with infused islet volumes and portal pressures but not platelet counts or other measures. Most thromboembolic events (82.7%) occurred before the postoperative day of maximum platelet count. Only 4 of 27 (14.8%) of portal vein thromboses occurred at platelet counts ≥500 × 109/L. Perioperative heparin was given to all patients. Treatment of reactive thrombocytosis using aspirin in adults and hydroxyurea in children was not associated with significantly decreased thromboembolic risk. CONCLUSIONS These results suggest that post-TPIAT thrombocytosis and portal vein thromboses may be linked to the islet infusion inflammation, not directly to each other, and further reducing this inflammation may reduce thrombosis and thrombocytosis frequencies simultaneously.
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Affiliation(s)
- Alexander A Boucher
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
| | - Solvejg Wastvedt
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN
| | - James S Hodges
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, MN
| | - Gregory J Beilman
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Varvara A Kirchner
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Timothy L Pruett
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Bernhard J Hering
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | | | - Elissa Downs
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
| | - Martin Freeman
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
| | - Guru Trikudanathan
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN
| | - Srinath Chinnakotla
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Melena D Bellin
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
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15
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Gao Q, Davis R, Fitch Z, Mulvihill M, Ezekian B, Schroder P, Schmitz R, Song M, Leopardi F, Ribeiro M, Miller A, Moris D, Shaw B, Samy K, Reimann K, Williams K, Collins B, Kirk AD. Anti-thymoglobulin induction improves neonatal porcine xenoislet engraftment and survival. Xenotransplantation 2021; 28:e12713. [PMID: 34951057 PMCID: PMC8715890 DOI: 10.1111/xen.12713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/13/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022]
Abstract
Porcine islet xenotransplantation is a viable strategy to treat diabetes. Its translation has been limited by the pre-clinical development of a clinically available immunosuppressive regimen. We tested two clinically relevant induction agents in a non-human primate (NHP) islet xenotransplantation model to compare depletional versus nondepletional induction immunosuppression. Neonatal porcine islets were isolated from GKO or hCD46/GKO transgenic piglets and transplanted via portal vein infusion in diabetic rhesus macaques. Induction therapy consisted of either basiliximab (n = 6) or rhesus-specific anti-thymocyte globulin (rhATG, n = 6), combined with a maintenance regimen using B7 costimulation blockade, tacrolimus with a delayed transition to sirolimus, and mycophenolate mofetil. Xenografts were monitored by blood glucose levels and porcine C-peptide measurements. Of the six receiving basiliximab induction, engraftment was achieved in 4 with median graft survival of 14 days. All six receiving rhATG induction engrafted with significantly longer xenograft survival at 40.5 days (P = 0.03). These data suggest that depletional induction provides superior xenograft survival to nondepletional induction, in the setting of a costimulation blockade-based maintenance regimen.
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Affiliation(s)
- Qimeng Gao
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Robert Davis
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Zachary Fitch
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Michael Mulvihill
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Brian Ezekian
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Paul Schroder
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Robin Schmitz
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Mingqing Song
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Frank Leopardi
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Marianna Ribeiro
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Allison Miller
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Dimitrios Moris
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Brian Shaw
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Kannan Samy
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Keith Reimann
- MassBiologics, University of Massachusetts Medical School, Worcester, Massachusetts, 01655, USA
| | - Kyha Williams
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Bradley Collins
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
| | - Allan D Kirk
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, 27710, USA
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16
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Chen C, Rawat D, Samikannu B, Bender M, Preissner KT, Linn T. Platelet glycoprotein VI-dependent thrombus stabilization is essential for the intraportal engraftment of pancreatic islets. Am J Transplant 2021; 21:2079-2089. [PMID: 33099857 DOI: 10.1111/ajt.16375] [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: 04/29/2020] [Revised: 09/15/2020] [Accepted: 10/09/2020] [Indexed: 01/25/2023]
Abstract
Platelet activation and thrombus formation have been implicated to be detrimental for intraportal pancreatic islet transplants. The platelet-specific collagen receptor glycoprotein VI (GPVI) plays a key role in thrombosis through cellular activation and the subsequent release of secondary mediators. In aggregometry and in a microfluidic dynamic assay system modeling flow in the portal vein, pancreatic islets promoted platelet aggregation and triggered thrombus formation, respectively. While platelet GPVI deficiency did not affect the initiation of these events, it was found to destabilize platelet aggregates and thrombi in this process. Interestingly, while no major difference was detected in early thrombus formation after intraportal islet transplantation, genetic GPVI deficiency or acute anti-GPVI treatment led to an inferior graft survival and function in both syngeneic mouse islet transplantation and xenogeneic human islet transplantation models. These results demonstrate that platelet GPVI signaling is indispensable in stable thrombus formation induced by pancreatic islets. GPVI deficiency resulted in thrombus destabilization and inferior islet engraftment indicating that thrombus formation is necessary for a successful intraportal islet transplantation in which platelets are active modulators.
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Affiliation(s)
- Chunguang Chen
- Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University, Giessen, Germany.,Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Divya Rawat
- Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University, Giessen, Germany
| | - Balaji Samikannu
- Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University, Giessen, Germany.,Cell and Developmental Biology, Weill Cornell Medicine Qatar, Doha, Qatar
| | - Markus Bender
- Institute of Experimental Biomedicine - Chair I, University Hospital and Rudolf Virchow Center, Würzburg, Germany
| | - Klaus T Preissner
- Department of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany
| | - Thomas Linn
- Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University, Giessen, Germany
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17
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Swentek L, Chung D, Ichii H. Antioxidant Therapy in Pancreatitis. Antioxidants (Basel) 2021; 10:657. [PMID: 33922756 PMCID: PMC8144986 DOI: 10.3390/antiox10050657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatitis is pathologic inflammation of the pancreas characterized by acinar cell destruction and oxidative stress. Repeated pancreatic insults can result in the development of chronic pancreatitis, characterized by irreversible fibrosis of the pancreas and many secondary sequelae, ultimately leading to the loss of this important organ. We review acute pancreatitis, chronic pancreatitis, and pancreatitis-related complications. We take a close look at the pathophysiology with a focus on oxidative stress and how it contributes to the complications of the disease. We also take a deep dive into the evolution and current status of advanced therapies for management including dietary modification, antioxidant supplementation, and nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1(Nrf2-keap1) pathway activation. In addition, we discuss the surgeries aimed at managing pain and preventing further endocrine dysfunction, such as total pancreatectomy with islet auto-transplantation.
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Affiliation(s)
| | | | - Hirohito Ichii
- Department of Surgery, University of California, Irvine, CA 92868, USA; (L.S.); (D.C.)
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18
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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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19
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Manay P, Turgeon N, Axelrod DA. Role of Whole Organ Pancreas Transplantation in the Day of Bioartificial and Artificial Pancreas. CURRENT TRANSPLANTATION REPORTS 2020. [DOI: 10.1007/s40472-020-00300-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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20
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Bai X, Pei Q, Pu C, Chen Y, He S, Wang B. Multifunctional Islet Transplantation Hydrogel Encapsulating A20 High-Expressing Islets. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:4021-4027. [PMID: 33061306 PMCID: PMC7532915 DOI: 10.2147/dddt.s273050] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/09/2020] [Indexed: 12/17/2022]
Abstract
Islet transplantation is regarded as the most promising treatment for type 1 diabetes (T1D). However, the function of grafted islet could be damaged on account of transplant rejection and/or hypoxia several years later after transplantation. We proposed a hypothetical functionalized hydrogel model, which encapsulates sufficient A20 high-expressing islets and supporting cells, and performs as a drug release system releasing immunosuppressants and growth factors, to improve the outcome of pancreatic islet transplantation. Once injected in vivo, the hydrogel can gel and offer a robust mechanical structure for the A20 high-expressing islets and supporting cells. The natural biomaterials (eg, heparin) added into the hydrogel provide adhesive sites for islets to promote islets’ survival. Furthermore, the hydrogel encapsulates various supporting cells, which can facilitate the vascularization and/or prevent the immune system attacking the islet graft. Based on the previous studies that generally applied one or two combined strategies to protect the function of islet graft, we designed this hypothetical multifunctional encapsulation hydrogel model with various functions. We hypothesized that the islet graft could survive and maintain its function for a longer time in vivo compared with naked islets. This hypothetical model has a limitation in terms of clinical application. Future development work will focus on verifying the function and safety of this hypothetical islet transplantation hydrogel model in vitro and in vivo.
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Affiliation(s)
- Xue Bai
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Qilin Pei
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Chunyi Pu
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Yi Chen
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Sirong He
- Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, People's Republic of China.,Chongqing Key Laboratory of Basic and Translational Research of Tumor Immunology, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Bin Wang
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, People's Republic of China
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21
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Shrestha P, Batra L, Tariq Malik M, Tan M, Yolcu ES, Shirwan H. Immune checkpoint CD47 molecule engineered islets mitigate instant blood-mediated inflammatory reaction and show improved engraftment following intraportal transplantation. Am J Transplant 2020; 20:2703-2714. [PMID: 32342638 DOI: 10.1111/ajt.15958] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/18/2020] [Accepted: 04/13/2020] [Indexed: 01/25/2023]
Abstract
Instant blood-mediated inflammatory reaction (IBMIR) causes significant destruction of islets transplanted intraportally. Myeloid cells are a major culprit of IBMIR. Given the critical role of CD47 as a negative checkpoint for myeloid cells, we hypothesized that the presence of CD47 on islets will minimize graft loss by mitigating IBMIR. We herein report the generation of a chimeric construct, SA-CD47, encompassing the extracellular domain of CD47 modified to include core streptavidin (SA). SA-CD47 protein was expressed in insect cells and efficiently displayed on biotin-modified mouse islet surface without a negative impact on their viability and function. Rat cells engineered with SA-CD47 were refractory to phagocytosis by mouse macrophages. SA-CD47-engineered islets showed intact structure and minimal infiltration by CD11b+ granulocytes/macrophages as compared with SA-engineered controls in an in vitro loop assay mitigating IBMIR. In a syngeneic marginal mass model of intraportal transplantation, SA-CD47-engineered islets showed better engraftment and function as compared with the SA-control group (87.5% vs 14.3%). Engraftment was associated with low levels of intrahepatic inflammatory cells and mediators of islet destruction, including high-mobility group box-1, tissue factor, and IL-1β. These findings support the use of CD47 as an innate immune checkpoint to mitigate IBMIR for enhanced islet engraftment with translational potential.
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Affiliation(s)
- Pradeep Shrestha
- Institute for Cellular Therapeutics and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Lalit Batra
- Institute for Cellular Therapeutics and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Mohammad Tariq Malik
- Institute for Cellular Therapeutics and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Min Tan
- Institute for Cellular Therapeutics and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Esma S Yolcu
- Institute for Cellular Therapeutics and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
- Department of Child Health, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Haval Shirwan
- Institute for Cellular Therapeutics and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA
- Department of Child Health, School of Medicine, University of Missouri, Columbia, Missouri, USA
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22
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Sykes M, Sachs DH. Transplanting organs from pigs to humans. Sci Immunol 2020; 4:4/41/eaau6298. [PMID: 31676497 DOI: 10.1126/sciimmunol.aau6298] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 10/02/2019] [Indexed: 12/20/2022]
Abstract
The success of organ transplantation is limited by the complications of immunosuppression, by chronic rejection, and by the insufficient organ supply, and thousands of patients die every year while waiting for a transplant. With recent progress in xenotransplantation permitting porcine organ graft survival of months or even years in nonhuman primates, there is renewed interest in its potential to alleviate the organ shortage. Many of these advances are the result of our heightened capacity to modify pigs genetically, particularly with the development of CRISPR-Cas9-based gene editing methodologies. Although this approach allows the engineering of pig organs that are less prone to rejection, the clinical application of xenotransplantation will require the ability to avoid the ravages of a multifaceted attack on the immune system while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. In this review, we will discuss the potential and limitations of these modifications and how the engineering of the graft can be leveraged to alter the host immune response so that all types of immune attack are avoided.
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Affiliation(s)
- Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA. .,Department of Microbiology and Immunology, Columbia University Medical Center, NY, USA.,Department of Surgery, Columbia University Medical Center, NY, USA
| | - David H Sachs
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA.,Department of Surgery, Columbia University Medical Center, NY, USA
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23
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Alcazar O, Hernandez LF, Nakayasu ES, Piehowski PD, Ansong C, Abdulreda MH, Buchwald P. Longitudinal proteomics analysis in the immediate microenvironment of islet allografts during progression of rejection. J Proteomics 2020; 223:103826. [PMID: 32442648 DOI: 10.1016/j.jprot.2020.103826] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022]
Abstract
The applicability and benefits of pancreatic islet transplantation are limited due to various issues including the need to avoid immune-mediated rejection. Here, we used our experimental platform of allogeneic islet transplant in the anterior chamber of the eye (ACE-platform) to longitudinally monitor the progress of rejection in mice and obtain aqueous humor samples representative of the microenvironment of the graft for accurately-timed proteomic analyses. LC-MS/MS-based proteomics performed on such mass-limited samples (~5 μL) identified a total of 1296 proteins. Various analyses revealed distinct protein patterns associated with the mounting of the inflammatory and immune responses and their evolution with the progression of the rejection. Pathway analyses indicated predominant changes in cytotoxic functions, cell movement, and innate and adaptive immune responses. Network prediction analyses revealed transition from humoral to cellular immune response and exacerbation of pro-inflammatory signaling. One of the proteins identified by this localized proteomics as a candidate biomarker of islet rejection, Cystatin 3, was further validated by ELISA in the aqueous humor. This study provides (1) experimental evidence demonstrating the feasibility of longitudinal localized proteomics using small aqueous humor samples and (2) proof-of-concept for the discovery of biomarkers of impending immune attack from the immediate local microenvironment of ACE-transplanted islets. SIGNIFICANCE: The combination of the ACE-platform and longitudinal localized proteomics offers a powerful approach to biomarker discovery during the various stages of immune reactions mounted against transplanted tissues including pancreatic islets. It also supports proteomics-assisted drug discovery and development efforts aimed at preventing rejection through efficacy assessment of new agents by noninvasive and longitudinal graft monitoring.
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Affiliation(s)
- Oscar Alcazar
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA
| | - Luis F Hernandez
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA
| | - Ernesto S Nakayasu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Paul D Piehowski
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Charles Ansong
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Midhat H Abdulreda
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Surgery, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Microbiology and Immunology, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Ophthalmology, Miami, FL, USA.
| | - Peter Buchwald
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Molecular and Cellular Pharmacology, Miami, FL, USA.
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24
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Potential Benefits of Nrf2/Keap1 Targeting in Pancreatic Islet Cell Transplantation. Antioxidants (Basel) 2020; 9:antiox9040321. [PMID: 32316115 PMCID: PMC7222398 DOI: 10.3390/antiox9040321] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/12/2020] [Accepted: 04/14/2020] [Indexed: 12/26/2022] Open
Abstract
Permanent pancreatic islet cell destruction occurs in type 1 diabetes mellitus (T1DM) through the infiltration of inflammatory cells and cytokines. Loss of β-cell integrity secondary to oxidation leads to an inability to appropriately synthesize and secrete insulin. Allogenic islet cell transplantation (ICT) has risen as a therapeutic option to mitigate problematic hypoglycemia. Nevertheless, during the process of transplantation, islet cells are exposed to oxidatively caustic conditions that severely decrease the islet cell yield. Islet cells are at a baseline disadvantage to sustain themselves during times of metabolic stress as they lack a robust anti-oxidant defense system, glycogen stores, and vascularity. The Nrf2/Keap1 system is a master regulator of antioxidant genes that has garnered attention as pharmacologic activators have shown a protective response and a low side effect profile. Herein, we present the most recently studied Nrf2/Keap1 activators in pancreas for application in ICT: Dh404, dimethyl fumarate (DMF), and epigallocatechin gallate (EGCG). Furthermore, we discuss that Nrf2/Keap1 is a potential target to ameliorate oxidative stress at every step of the Edmonton Protocol.
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25
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Stabler CL, Giraldo JA, Berman DM, Gattás-Asfura KM, Willman MA, Rabassa A, Geary J, Diaz W, Kenyon NM, Kenyon NS. Transplantation of PEGylated islets enhances therapeutic efficacy in a diabetic nonhuman primate model. Am J Transplant 2020; 20:689-700. [PMID: 31597005 PMCID: PMC7042048 DOI: 10.1111/ajt.15643] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/19/2019] [Accepted: 09/29/2019] [Indexed: 01/25/2023]
Abstract
Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti-inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long-chain poly(ethylene glycol) (PEG) to mitigate detrimental host-implant interactions. The effect of PEGylation on islet engraftment and long-term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti-thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC-matched recipients and received MHC-disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c-peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.
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Affiliation(s)
- CL Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL USA,Diabetes Research Institute, University of Miami, Miami, FL USA,Corresponding Authors: Prof Cherie Stabler, ; Prof Norma Kenyon,
| | - JA Giraldo
- Diabetes Research Institute, University of Miami, Miami, FL USA
| | - DM Berman
- Diabetes Research Institute, University of Miami, Miami, FL USA,Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136
| | - KM Gattás-Asfura
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL USA,Diabetes Research Institute, University of Miami, Miami, FL USA
| | - MA Willman
- Diabetes Research Institute, University of Miami, Miami, FL USA
| | - A Rabassa
- Diabetes Research Institute, University of Miami, Miami, FL USA
| | - J Geary
- Diabetes Research Institute, University of Miami, Miami, FL USA
| | - W Diaz
- Diabetes Research Institute, University of Miami, Miami, FL USA
| | - NM Kenyon
- Diabetes Research Institute, University of Miami, Miami, FL USA
| | - NS Kenyon
- Diabetes Research Institute, University of Miami, Miami, FL USA,Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136,Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136,Biomedical Engineering, University of Miami, Miami, FL 33136,Corresponding Authors: Prof Cherie Stabler, ; Prof Norma Kenyon,
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26
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Palomo M, Blasco M, Molina P, Lozano M, Praga M, Torramade-Moix S, Martinez-Sanchez J, Cid J, Escolar G, Carreras E, Paules C, Crispi F, Quintana LF, Poch E, Rodas L, Goma E, Morelle J, Espinosa M, Morales E, Avila A, Cabello V, Ariceta G, Chocron S, Manrique J, Barros X, Martin N, Huerta A, Fraga-Rodriguez GM, Cao M, Martin M, Romera AM, Moreso F, Manonelles A, Gratacos E, Pereira A, Campistol JM, Diaz-Ricart M. Complement Activation and Thrombotic Microangiopathies. Clin J Am Soc Nephrol 2019; 14:1719-1732. [PMID: 31694864 PMCID: PMC6895490 DOI: 10.2215/cjn.05830519] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 10/02/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVES Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included. RESULTS Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. CONCLUSIONS The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.
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Affiliation(s)
- Marta Palomo
- Josep Carreras Leukaemia Research Institute; .,Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.,Barcelona Endothelium Team, Barcelona, Spain
| | - Miquel Blasco
- Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain.,Group of nephro-urological diseases and renal transplantation (IDIBAPS), Barcelona, Spain
| | - Patricia Molina
- Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
| | - Miquel Lozano
- Apheresis Unit, Department of Hemotherapy and Hemostasis, Institut Clinic de Malalties Hematologiques i Oncologiques (ICMHO), IDIBAPS, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain
| | - Manuel Praga
- Department of Nephrology, Hospital Universitario 12 de Octubre and Research Institute i+12, Madrid, Spain.,Department of Medicine, Universidad Complutense, Madrid, Spain
| | - Sergi Torramade-Moix
- Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
| | - Julia Martinez-Sanchez
- Josep Carreras Leukaemia Research Institute.,Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.,Barcelona Endothelium Team, Barcelona, Spain
| | - Joan Cid
- Apheresis Unit, Department of Hemotherapy and Hemostasis, Institut Clinic de Malalties Hematologiques i Oncologiques (ICMHO), IDIBAPS, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain
| | - Gines Escolar
- Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
| | - Enric Carreras
- Josep Carreras Leukaemia Research Institute.,Barcelona Endothelium Team, Barcelona, Spain
| | - Cristina Paules
- Fetal i+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clinic de Barcelona and Hospital Sant Joan de Deu), ICGON, IDIBAPS, Universitat de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Barcelona, Spain
| | - Fatima Crispi
- Fetal i+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clinic de Barcelona and Hospital Sant Joan de Deu), ICGON, IDIBAPS, Universitat de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Barcelona, Spain
| | - Luis F Quintana
- Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain.,Group of nephro-urological diseases and renal transplantation (IDIBAPS), Barcelona, Spain
| | - Esteban Poch
- Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain.,Group of nephro-urological diseases and renal transplantation (IDIBAPS), Barcelona, Spain
| | - Lida Rodas
- Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain
| | - Emma Goma
- Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain
| | - Johann Morelle
- Division of Nephrology, Cliniques universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Mario Espinosa
- Department of Nephrology, Hospital Universitario Reina Sofía e Instituto Maimonides de Investigaciones Biológicas de Córdoba (IMIBIC), Córdoba, Spain
| | - Enrique Morales
- Department of Nephrology, Hospital Universitario 12 de Octubre and Research Institute i+12, Madrid, Spain
| | - Ana Avila
- Department of Nephrology and Renal Transplantation, Hospital Universitario Dr Peset, Valencia, Spain
| | - Virginia Cabello
- Department of Nephrology, Hospital Virgen del Rocio, Sevilla, Spain
| | - Gema Ariceta
- Department of Pediatric Nephrology, Hospital Materno-Infantil, Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Sara Chocron
- Department of Pediatric Nephrology, Hospital Materno-Infantil, Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Joaquin Manrique
- Department of Nephrology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Xoana Barros
- Department of Nephrology, Hospital Universitari Josep Trueta, Girona, Spain
| | - Nadia Martin
- Department of Nephrology, Hospital Universitari Josep Trueta, Girona, Spain
| | - Ana Huerta
- Department of Nephrology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain
| | - Gloria M Fraga-Rodriguez
- Department of Pediatric Nephrology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Mercedes Cao
- Department of Nephrology, Complejo Hospitalario Universitario A Coruña, Coruña, Spain
| | - Marisa Martin
- Department of Nephrology, Hospital Universitari Arnau de Vilanova, Lleida, Spain
| | - Ana Maria Romera
- Department of Nephrology, Hospital General Universitario, Ciudad Real, Spain
| | - Francesc Moreso
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autonoma Barcelona, Barcelona, Spain
| | - Anna Manonelles
- Kidney Transplant Unit, Department of Nephrology, Hospital de Bellvitge, Universitat de Barcelona, Barcelona, Spain; and
| | - Eduard Gratacos
- Fetal i+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clinic de Barcelona and Hospital Sant Joan de Deu), ICGON, IDIBAPS, Universitat de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Barcelona, Spain
| | | | - Josep M Campistol
- Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain
| | - Maribel Diaz-Ricart
- Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.,Barcelona Endothelium Team, Barcelona, Spain
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27
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Coppin L, Sokal E, Stéphenne X. Thrombogenic Risk Induced by Intravascular Mesenchymal Stem Cell Therapy: Current Status and Future Perspectives. Cells 2019; 8:cells8101160. [PMID: 31569696 PMCID: PMC6829440 DOI: 10.3390/cells8101160] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are currently studied and used in numerous clinical trials. Nevertheless, some concerns have been raised regarding the safety of these infusions and the thrombogenic risk they induce. MSCs express procoagulant activity (PCA) linked to the expression of tissue factor (TF) that, when in contact with blood, initiates coagulation. Some even describe a dual activation of both the coagulation and the complement pathway, called Instant Blood-Mediated Inflammatory Reaction (IBMIR), explaining the disappointing results and low engraftment rates in clinical trials. However, nowadays, different approaches to modulate the PCA of MSCs and thus control the thrombogenic risk after cell infusion are being studied. This review summarizes both in vitro and in vivo studies on the PCA of MSC of various origins. It further emphasizes the crucial role of TF linked to the PCA of MSCs. Furthermore, optimization of MSC therapy protocols using different methods to control the PCA of MSCs are described.
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Affiliation(s)
- Louise Coppin
- Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
| | - Etienne Sokal
- Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
| | - Xavier Stéphenne
- Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
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28
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Bowers DT, Song W, Wang LH, Ma M. Engineering the vasculature for islet transplantation. Acta Biomater 2019; 95:131-151. [PMID: 31128322 PMCID: PMC6824722 DOI: 10.1016/j.actbio.2019.05.051] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/13/2019] [Accepted: 05/20/2019] [Indexed: 12/17/2022]
Abstract
The microvasculature in the pancreatic islet is highly specialized for glucose sensing and insulin secretion. Although pancreatic islet transplantation is a potentially life-changing treatment for patients with insulin-dependent diabetes, a lack of blood perfusion reduces viability and function of newly transplanted tissues. Functional vasculature around an implant is not only necessary for the supply of oxygen and nutrients but also required for rapid insulin release kinetics and removal of metabolic waste. Inadequate vascularization is particularly a challenge in islet encapsulation. Selectively permeable membranes increase the barrier to diffusion and often elicit a foreign body reaction including a fibrotic capsule that is not well vascularized. Therefore, approaches that aid in the rapid formation of a mature and robust vasculature in close proximity to the transplanted cells are crucial for successful islet transplantation or other cellular therapies. In this paper, we review various strategies to engineer vasculature for islet transplantation. We consider properties of materials (both synthetic and naturally derived), prevascularization, local release of proangiogenic factors, and co-transplantation of vascular cells that have all been harnessed to increase vasculature. We then discuss the various other challenges in engineering mature, long-term functional and clinically viable vasculature as well as some emerging technologies developed to address them. The benefits of physiological glucose control for patients and the healthcare system demand vigorous pursuit of solutions to cell transplant challenges. STATEMENT OF SIGNIFICANCE: Insulin-dependent diabetes affects more than 1.25 million people in the United States alone. Pancreatic islets secrete insulin and other endocrine hormones that control glucose to normal levels. During preparation for transplantation, the specialized islet blood vessel supply is lost. Furthermore, in the case of cell encapsulation, cells are protected within a device, further limiting delivery of nutrients and absorption of hormones. To overcome these issues, this review considers methods to rapidly vascularize sites and implants through material properties, pre-vascularization, delivery of growth factors, or co-transplantation of vessel supporting cells. Other challenges and emerging technologies are also discussed. Proper vascular growth is a significant component of successful islet transplantation, a treatment that can provide life-changing benefits to patients.
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Affiliation(s)
- Daniel T Bowers
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Wei Song
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Long-Hai Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
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29
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Stabler CL, Li Y, Stewart JM, Keselowsky BG. Engineering immunomodulatory biomaterials for type 1 diabetes. NATURE REVIEWS. MATERIALS 2019; 4:429-450. [PMID: 32617176 PMCID: PMC7332200 DOI: 10.1038/s41578-019-0112-5] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
A cure for type 1 diabetes (T1D) would help millions of people worldwide, but remains elusive thus far. Tolerogenic vaccines and beta cell replacement therapy are complementary therapies that seek to address aberrant T1D autoimmune attack and subsequent beta cell loss. However, both approaches require some form of systematic immunosuppression, imparting risks to the patient. Biomaterials-based tools enable localized and targeted immunomodulation, and biomaterial properties can be designed and combined with immunomodulatory agents to locally instruct specific immune responses. In this Review, we discuss immunomodulatory biomaterial platforms for the development of T1D tolerogenic vaccines and beta cell replacement devices. We investigate nano- and microparticles for the delivery of tolerogenic agents and autoantigens, and as artificial antigen presenting cells, and highlight how bulk biomaterials can be used to provide immune tolerance. We examine biomaterials for drug delivery and as immunoisolation devices for cell therapy and islet transplantation, and explore synergies with other fields for the development of new T1D treatment strategies.
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Affiliation(s)
- CL Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
- Interdisciplinary Graduate Program in Biomedical Sciences, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Y Li
- Interdisciplinary Graduate Program in Biomedical Sciences, University of Florida, Gainesville, FL, USA
| | - JM Stewart
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - BG Keselowsky
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
- Interdisciplinary Graduate Program in Biomedical Sciences, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, Gainesville, FL, USA
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Gurria JP, Boucher AA, Hornung L, Palumbo JS, Badia P, Luchtman-Jones L, Abu-El-Haija M, Lin TK, Nathan JD. Thrombopoietin Contributes to Extreme Thrombocytosis After Pediatric Pancreatectomy With Islet Autotransplantation. Pancreas 2019; 48:652-655. [PMID: 31091211 DOI: 10.1097/mpa.0000000000001313] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE This study aims to explore the role of thrombopoietin (TPO) production in extreme thrombocytosis that is often observed after pancreatectomy with islet autotransplantation (IAT) and the effectiveness of hydroxyurea in thrombocytosis management. METHODS Retrospective chart review was performed for all patients who underwent pancreatectomy with IAT at our institution between April 1, 2015, and December 31, 2016. Data evaluated included demographics, platelet counts, TPO levels, and thrombocytosis management strategies. RESULTS Twelve total and 1 subtotal pancreatectomy with IAT cases were reviewed. All operations included splenectomy. No major surgical or thrombotic complications occurred. Thrombopoietin levels, normal preoperatively, rose significantly (median, 219 pg/mL) soon after surgery, peaking on median postoperative day 3. Platelet counts, also normal preoperatively, increased within a week of surgery, with 92% over 1000 K/μL (median peak platelet count, 1403 K/μL). Platelet counts and TPO levels dropped after hydroxyurea initiation in most patients. CONCLUSIONS After pancreatectomy with IAT, patients experienced marked TPO rise and subsequent thrombocytosis, and both decreased significantly after hydroxyurea initiation. These data suggest that TPO elevation and associated increased platelet production may be one driver of early extreme post-total pancreatectomy with islet autotransplantation thrombocytosis, and this process may be modulated by hydroxyurea.
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Affiliation(s)
- Juan P Gurria
- From the Division of Pediatric General and Thoracic Surgery
| | | | - Lindsey Hornung
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital
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Kosinova L, Patikova A, Jirak D, Galisova A, Vojtiskova A, Saudek F, Kriz J. A novel model for in vivo quantification of immediate liver perfusion impairment after pancreatic islet transplantation. Islets 2019; 11:129-140. [PMID: 31498024 PMCID: PMC6930024 DOI: 10.1080/19382014.2019.1651164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Instant Blood-Mediated Inflammatory Reaction (IBMIR) is a major cause of graft loss during pancreatic islet transplantation, leading to a low efficiency of this treatment method and significantly limiting its broader clinical use. Within the procedure, transplanted islets obstruct intrahepatic portal vein branches and consequently restrict blood supply of downstream lying liver tissue, resulting typically in ischemic necrosis. The extent of ischemic lesions is influenced by mechanical obstruction and inflammation, as well as subsequent recanalization and regeneration capacity of recipient liver tissue. Monitoring of immediate liver perfusion impairment, which is directly related to the intensity of post-transplant inflammation and thrombosis (IBMIR), is essential for improving therapeutic and preventive strategies to improve overall islet graft survival. In this study, we present a new experimental model enabling direct quantification of liver perfusion impairment after pancreatic islet transplantation using ligation of hepatic arteries followed by contrast-enhanced magnetic resonance imaging (MRI). The ligation of hepatic arteries prevents the contrast agent from circumventing the portal vein obstruction and enables to discriminate between well-perfused and non-perfused liver tissue. Here we demonstrate that the extent of liver ischemia reliably reflects the number of transplanted islets. This model represents a useful tool for in vivo monitoring of biological effect of IBMIR-alleviating interventions as well as other experiments related to liver ischemia. This technical paper introduces a novel technique and its first application in experimental animals.
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Affiliation(s)
- Lucie Kosinova
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Faculty of Medicine, Charles University, Prague, Czech Republic
- CONTACT Jan Kriz Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague, Czech Republic
| | - Alzbeta Patikova
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Daniel Jirak
- Magnetic Resonance Unit, Radiodiagnostic and Interventional Radiology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Institute of Biophysics and Informatics, Charles University, Prague, Czech Republic
| | - Andrea Galisova
- Magnetic Resonance Unit, Radiodiagnostic and Interventional Radiology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alzbeta Vojtiskova
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Frantisek Saudek
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jan Kriz
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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Groot Nibbelink M, Skrzypek K, Karbaat L, Both S, Plass J, Klomphaar B, van Lente J, Henke S, Karperien M, Stamatialis D, van Apeldoorn A. An important step towards a prevascularized islet microencapsulation device: in vivo prevascularization by combination of mesenchymal stem cells on micropatterned membranes. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2018; 29:174. [PMID: 30413974 PMCID: PMC6244873 DOI: 10.1007/s10856-018-6178-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 10/17/2018] [Indexed: 06/08/2023]
Abstract
Extrahepatic transplantation of islets of Langerhans could aid in better survival of islets after transplantation. When islets are transfused into the liver 60-70% of them are lost immediately after transplantation. An important factor for a successful extrahepatic transplantation is a well-vascularized tissue surrounding the implant. There are many strategies known for enhancing vessel formation such as adding cells with endothelial potential, the combination with angiogenic factors and / or applying surface topography at the exposed surface of the device. Previously we developed porous, micropatterned membranes which can be applied as a lid for an islet encapsulation device and we showed that the surface topography induces human umbilical vein endothelial cell (HUVEC) alignment and interconnection. This was achieved without the addition of hydrogels, often used in angiogenesis assays. In this work, we went one step further towards clinical implementation of the device by combining this micropatterned lid with Mesenchymal Stem Cells (MSCs) to facilitate prevascularization in vivo. As for HUVECs, the micropatterned membranes induced MSC alignment and organization in vitro, an important contributor to vessel formation, whereas in vivo (subcutaneous rat model) they contributed to improved implant prevascularization. In fact, the combination of MSCs seeded on the micropatterned membrane induced the highest vessel formation score in 80% of the sections.
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Affiliation(s)
- Milou Groot Nibbelink
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands.
| | - Katarzyna Skrzypek
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Lisanne Karbaat
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Sanne Both
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Jacqueline Plass
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Bettie Klomphaar
- Biomedical Signals and Systems, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Jéré van Lente
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Sieger Henke
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Marcel Karperien
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Dimitrios Stamatialis
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Aart van Apeldoorn
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
- Complex Tissue Regeneration, MERLN Institute for Technology Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
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Abstract
First described in the early 1980s, total pancreatectomy with autologous islet cell transplantation for the treatment of chronic pancreatitis is still only offered in select centers worldwide. Indications, process details including surgery as well as islet isolation, and results are reviewed. In addition, areas for further research to optimize results are identified.
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Affiliation(s)
- Beth Schrope
- Department of Surgery, Columbia University College of Physicians and Surgeons, 161 Fort Washington Avenue, 8th Floor, New York, NY 10032, USA.
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Song G, Hu Y, Liu Y, Jiang R. Layer-by-Layer Heparinization of the Cell Surface by Using Heparin-Binding Peptide Functionalized Human Serum Albumin. MATERIALS 2018; 11:ma11050849. [PMID: 29783776 PMCID: PMC5978226 DOI: 10.3390/ma11050849] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 05/17/2018] [Accepted: 05/18/2018] [Indexed: 02/07/2023]
Abstract
Layer-by-layer heparinization of therapeutic cells prior to transplantation is an effective way to inhibit the instant blood-mediated inflammatory reactions (IBMIRs), which are the major cause of early cell graft loss during post-transplantation. Here, a conjugate of heparin-binding peptide (HBP) and human serum albumin (HSA), HBP-HSA, was synthesized by using heterobifunctional crosslinker. After the first heparin layer was coated on human umbilical vein endothelial cells (HUVECs) by means of the HBP-polyethylene glycol-phospholipid conjugate, HBP-HSA and heparin were then applied to the cell surface sequentially to form multiple layers. The immobilization and retention of heparin were analyzed by confocal microscopy and flow cytometry, respectively, and the cytotoxity of HBP-HSA was further evaluated by cell viability assay. Results indicated that heparin was successfully introduced to the cell surface in a layer-by-layer way and retained for at least 24 h, while the cytotoxity of HBP-HSA was negligible at the working concentration. Accordingly, this conjugate provides a promising method for co-immobilization of heparin and HSA to the cell surface under physiological conditions with improved biocompatibility.
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Affiliation(s)
- Guowei Song
- College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China.
| | - Yaning Hu
- College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China.
| | - Yusheng Liu
- College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China.
| | - Rui Jiang
- College of Life and Health Sciences, Northeastern University, Shenyang, 110169, China.
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Park H, Haque MR, Park JB, Lee KW, Lee S, Kwon Y, Lee HS, Kim GS, Shin DY, Jin SM, Kim JH, Kang HJ, Byun Y, Kim SJ. Polymeric nano-shielded islets with heparin-polyethylene glycol in a non-human primate model. Biomaterials 2018; 171:164-177. [PMID: 29698867 DOI: 10.1016/j.biomaterials.2018.04.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 04/11/2018] [Accepted: 04/14/2018] [Indexed: 10/17/2022]
Abstract
Intraportal pancreatic islet transplantation incurs huge cell losses during its early stages due to instant blood-mediated inflammatory reactions (IBMIRs), which may also drive regulation of the adaptive immune system. Therefore, a method that evades IBMIR will improve clinical islet transplantation. We used a layer-by-layer approach to shield non-human primate (NHP) islets with polyethylene glycol (nano-shielded islets, NSIs) and polyethylene glycol plus heparin (heparin nano-shielded islets; HNSIs). Islets ranging from 10,000 to 20,000 IEQ/kg body weight were transplanted into 19 cynomolgus monkeys (n = 4, control; n = 5, NSI; and n = 10, HNSI). The mean C-peptide positive graft survival times were 68.5, 64 and 108 days for the control, NSI and HNSI groups, respectively (P = 0.012). HNSI also reduced the factors responsible for IBMIR in vitro. Based on these data, HNSIs in conjunction with clinically established immunosuppressive drug regimens will result in superior outcomes compared to those achieved with the current protocol for clinical islet transplantation.
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Affiliation(s)
- Hyojun Park
- Department of Surgery, VHS Medical Center, Seoul 05368, Republic of Korea
| | - Muhammad R Haque
- Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Kyo Won Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Yeongbeen Kwon
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea
| | - Han Sin Lee
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea
| | - Geun-Soo Kim
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea
| | - Du Yeon Shin
- Transplantation Research Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea
| | - Sang-Man Jin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Hee Jung Kang
- Department of Laboratory Medicine, Hallym University College of Medicine, Anyang-si, Republic of Korea
| | - Youngro Byun
- Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
| | - Sung Joo Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul 06351, Republic of Korea.
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Lee EM, Jung JI, Alam Z, Yi HG, Kim H, Choi JW, Hurh S, Kim YJ, Jeong JC, Yang J, Oh KH, Kim HC, Lee BC, Choi I, Cho DW, Ahn C. Effect of an oxygen-generating scaffold on the viability and insulin secretion function of porcine neonatal pancreatic cell clusters. Xenotransplantation 2018; 25:e12378. [DOI: 10.1111/xen.12378] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/15/2017] [Accepted: 11/24/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Eun Mi Lee
- Graduate School of Translational Medicine; Seoul National University College of Medicine; Seoul Korea
- Center for Medical Innovation; Biomedical Research Institute; Seoul National University Hospital; Seoul Korea
| | - Ji-In Jung
- Department of Mechanical Engineering; Pohang University of Science and Technology (POSTECH); Pohang Gyeongsangbuk-do Korea
| | - Zahid Alam
- Center for Medical Innovation; Biomedical Research Institute; Seoul National University Hospital; Seoul Korea
| | - Hee-Gyeong Yi
- Department of Mechanical Engineering; Pohang University of Science and Technology (POSTECH); Pohang Gyeongsangbuk-do Korea
| | - Heejin Kim
- Interdisciplinary Program in Bioengineering; Graduate School; Seoul National University; Seoul Korea
| | - Jin Woo Choi
- Interdisciplinary Program in Bioengineering; Graduate School; Seoul National University; Seoul Korea
| | - Sunghoon Hurh
- Center for Medical Innovation; Biomedical Research Institute; Seoul National University Hospital; Seoul Korea
| | - Young June Kim
- Designed Animal & Transplantation Research Institute; Institute of Green Bio Science & Technology; Seoul National University; Pyeongchang Gangwon-do Korea
| | - Jong Cheol Jeong
- Department of Nephrology; Ajou University School of Medicine; Suwon Gyeonggi-do Korea
| | - Jaeseok Yang
- Transplantation Center; Seoul National University Hospital; Seoul Korea
- Department of Surgery; Seoul National University Hospital; Seoul Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
| | - Hee Chan Kim
- Department of Biomedical Engineering; Seoul National University College of Medicine; Seoul Korea
| | - Byeong Chun Lee
- Designed Animal & Transplantation Research Institute; Institute of Green Bio Science & Technology; Seoul National University; Pyeongchang Gangwon-do Korea
- Department of Theriogenology and Biotechnology; College of Veterinary Medicine; Seoul National University; Seoul Korea
| | - Inho Choi
- Department of Pharmaceutical Engineering; College of Life and Health Sciences; Hoseo University; Asan Chungcheongnam-do Korea
| | - Dong-Woo Cho
- Department of Mechanical Engineering; Pohang University of Science and Technology (POSTECH); Pohang Gyeongsangbuk-do Korea
| | - Curie Ahn
- Designed Animal & Transplantation Research Institute; Institute of Green Bio Science & Technology; Seoul National University; Pyeongchang Gangwon-do Korea
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
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38
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Desai CS, Khan KM, Ma X, Li H, Wang J, Fan L, Chen G, Smith JP, Cui W. Effect of liver histopathology on islet cell engraftment in the model mimicking autologous islet cell transplantation. Islets 2017; 9:140-149. [PMID: 28902579 PMCID: PMC5710696 DOI: 10.1080/19382014.2017.1356558] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND The inflammatory milieu in the liver as determined by histopathology is different in individual patients undergoing autologous islet cell transplantation. We hypothesized that inflammation related to fatty-liver adversely impacts islet survival. To test this hypothesis, we used a mouse model of fatty-liver to determine the outcome of syngeneic islet transplantation after chemical pancreatectomy. METHODS Mice (C57BL/6) were fed a high-fat-diet from 6 weeks of age until attaining a weight of ≥28 grams (6-8 weeks) to produce a fatty liver (histologically > 30% fat);steatosis was confirmed with lipidomic profile of liver tissue. Islets were infused via the intra-portal route in fatty-liver and control mice after streptozotocin induction of diabetes. Outcomes were assessed by the rate of euglycemia, liver histopathology, evaluation of liver inflammation by measuring tissue cytokines IL-1β and TNF-α by RT-PCR and CD31 expression by immunohistochemistry. RESULTS The difference in the euglycemic fraction between the normal liver group (90%, 9/10) and the fatty-liver group (37.5%, 3/8) was statistically significant at the 18th day post- transplant and was maintained to the end of the study (day 28) (p = 0.019, X2 = 5.51). Levels of TNF-α and IL-1β were elevated in fatty-liver mice (p = 0.042, p = 0.037). Compared to controls cytokine levels were elevated after islet cell transplantation and in transplanted fatty-liver mice as compared to either fatty- or islet transplant group alone (p = NS). A difference in the histochemical pattern of CD31 could not be determined. CONCLUSION Fatty-liver creates an inflammatory state which adversely affects the outcome of autologous islet cell transplantation.
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Affiliation(s)
- Chirag S. Desai
- Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
- CONTACT Chirag S. Desai Department of Surgery, University of North Carolina4021 Burnett Womack Building, Campus Box 7211, Chapel Hill, NC 27599, USA
| | - Khalid M. Khan
- Medstar Georgetown Transplant Institute, Washington DC, USA
| | - Xiaobo Ma
- Islet Cell Laboratory, Medstar Georgetown University Hospital, Washington DC, USA
| | - Henghong Li
- Department of Medicine, Georgetown University Medical Center, Washington DC, USA
| | - Juan Wang
- Department of Medicine, Georgetown University Medical Center, Washington DC, USA
| | - Lijuan Fan
- Department of Medicine, Georgetown University Medical Center, Washington DC, USA
| | - Guoling Chen
- Islet Cell Laboratory, Medstar Georgetown University Hospital, Washington DC, USA
| | - Jill P. Smith
- Department of Medicine, Georgetown University Medical Center, Washington DC, USA
| | - Wanxing Cui
- Islet Cell Laboratory, Medstar Georgetown University Hospital, Washington DC, USA
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Yoshimatsu G, Kunnathodi F, Saravanan PB, Shahbazov R, Chang C, Darden CM, Zurawski S, Boyuk G, Kanak MA, Levy MF, Naziruddin B, Lawrence MC. Pancreatic β-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation. Diabetes 2017; 66:2857-2867. [PMID: 28855240 PMCID: PMC5652609 DOI: 10.2337/db17-0578] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/22/2017] [Indexed: 01/08/2023]
Abstract
Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these "isletokines" in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-γ-induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet-specific expression of IP-10 contributed to islet inflammation and loss of β-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti-IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic β-cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in β-cells and reveal IP-10 as a primary therapeutic target to prevent β-cell-induced inflammatory loss of graft function after islet cell transplantation.
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Affiliation(s)
| | | | | | - Rauf Shahbazov
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX
| | - Charles Chang
- Institute of Biomedical Studies, Baylor University, Waco, TX
| | - Carly M Darden
- Institute of Biomedical Studies, Baylor University, Waco, TX
| | | | - Gulbahar Boyuk
- Adacell Medical Research Center, Department of Endocrinology and Metabolism, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
| | - Mazhar A Kanak
- Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Marlon F Levy
- Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA
| | - Bashoo Naziruddin
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX
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Kreutter G, Kassem M, El Habhab A, Baltzinger P, Abbas M, Boisrame‐Helms J, Amoura L, Peluso J, Yver B, Fatiha Z, Ubeaud‐Sequier G, Kessler L, Toti F. Endothelial microparticles released by activated protein C protect beta cells through EPCR/PAR1 and annexin A1/FPR2 pathways in islets. J Cell Mol Med 2017; 21:2759-2772. [PMID: 28524456 PMCID: PMC5661261 DOI: 10.1111/jcmm.13191] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 03/12/2017] [Indexed: 01/08/2023] Open
Abstract
Islet transplantation is associated with early ischaemia/reperfusion, localized coagulation and redox-sensitive endothelial dysfunction. In animal models, islet cytoprotection by activated protein C (aPC) restores islet vascularization and protects graft function, suggesting that aPC triggers various lineages. aPC also prompts the release of endothelial MP that bear EPCR, its specific receptor. Microparticles (MP) are plasma membrane procoagulant vesicles, surrogate markers of stress and cellular effectors. We measured the cytoprotective effects of aPC on endothelial and insulin-secreting Rin-m5f β-cells and its role in autocrine and paracrine MP-mediated cell crosstalk under conditions of oxidative stress. MP from aPC-treated primary endothelial (EC) or β-cells were applied to H2 O2 -treated Rin-m5f. aPC activity was measured by enzymatic assay and ROS species by dihydroethidium. The capture of PKH26-stained MP and the expression of EPCR were probed by fluorescence microscopy and apoptosis by flow cytometry. aPC treatment enhanced both annexin A1 (ANXA1) and PAR-1 expression in EC and to a lesser extent in β-cells. MP from aPC-treated EC (eMaPC ) exhibited high EPCR and annexin A1 content, protected β-cells, restored insulin secretion and were captured by 80% of β cells in a phosphatidylserine and ANXA1-dependent mechanism. eMP activated EPCR/PAR-1 and ANXA1/FPR2-dependent pathways and up-regulated the expression of EPCR, and of FPR2/ALX, the ANXA1 receptor. Cytoprotection was confirmed in H2 O2 -treated rat islets with increased viability (62% versus 48% H2 O2 ), reduced apoptosis and preserved insulin secretion in response to glucose elevation (16 versus 5 ng/ml insulin per 10 islets). MP may prove a promising therapeutic tool in the protection of transplanted islets.
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Affiliation(s)
- Guillaume Kreutter
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
| | - Mohamad Kassem
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- UMR7213 CNRSLaboratory of Biophotonics and PharmacologyFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
| | - Ali El Habhab
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- UMR7213 CNRSLaboratory of Biophotonics and PharmacologyFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
| | - Philippe Baltzinger
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- Department of DiabetologyUniversity HospitalCHU de Strasbourg1 place de l'HôpitalStrasbourg CedexFrance
| | - Malak Abbas
- UMR7213 CNRSLaboratory of Biophotonics and PharmacologyFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
| | - Julie Boisrame‐Helms
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- Department of Anesthesia‐ReanimationUniversity Hospital, CHU de Strasbourg, 1 place de l'HôpitalStrasbourg CedexFrance
| | - Lamia Amoura
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- UMR7213 CNRSLaboratory of Biophotonics and PharmacologyFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
| | - Jean Peluso
- UPS1401‐ Plateforme eBiocyteFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
| | - Blandine Yver
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
| | - Zobairi Fatiha
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
| | - Geneviève Ubeaud‐Sequier
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- Department of Pharmacy‐sterilizationUniversity HospitalCHU de StrasbourgStrasbourgFrance
- UPS1401‐ Plateforme eBiocyteFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
| | - Laurence Kessler
- EA7293Vascular and Tissular Stress in TransplantationFederation of Translational Medicine of StrasbourgFaculty of MedicineUniversity of StrasbourgIllkirchFrance
- Department of DiabetologyUniversity HospitalCHU de Strasbourg1 place de l'HôpitalStrasbourg CedexFrance
| | - Florence Toti
- UMR7213 CNRSLaboratory of Biophotonics and PharmacologyFaculty of PharmacyUniversity of StrasbourgIllkirchFrance
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Wu Z, Zhang S, Zhou L, Cai J, Tan J, Gao X, Zeng Z, Li D. Thromboembolism Induced by Umbilical Cord Mesenchymal Stem Cell Infusion: A Report of Two Cases and Literature Review. Transplant Proc 2017; 49:1656-1658. [PMID: 28838459 DOI: 10.1016/j.transproceed.2017.03.078] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 11/16/2016] [Accepted: 03/15/2017] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the thromboembolism induced by blood-mediated inflammatory reactions against infused cells during the clinical application of stem cells. METHODS Two patients with renal transplantation and chronic kidney disease, respectively, experienced thromboembolism after umbilical cord mesenchymal stem cell (UCMSC) infusion. The clinical manifestations and the laboratory test results were collected and analyzed. RESULTS The patients received stem cell infusion through the peripheral veins and presented with a swollen and painful forearm postinfusion. Doppler ultrasound showed venous clots at the proximal end of the puncture site. Urokinase and warfarin were used for thrombolytic therapy. The swelling and pain were relieved and cured. CONCLUSION Safety concerns are still a primary hurdle for stem cell therapy, and thromboembolism as a critical complication should be prevented appropriately.
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Affiliation(s)
- Z Wu
- Department of Hepatobiliary Disease, Fuzhou General Hospital (Donfang Hospital), Xiamen University, Fuzhou, China
| | - S Zhang
- Department of Hepatobiliary Disease, Fuzhou General Hospital (Donfang Hospital), Xiamen University, Fuzhou, China
| | - L Zhou
- Department of Hepatobiliary Disease, Fuzhou General Hospital (Donfang Hospital), Xiamen University, Fuzhou, China
| | - J Cai
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, China
| | - J Tan
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, China
| | - X Gao
- Organ Transplant Institute, Fuzhou General Hospital (Dongfang Hospital), Xiamen University, Fuzhou, China
| | - Z Zeng
- Department of Hepatobiliary Disease, Fuzhou General Hospital (Donfang Hospital), Xiamen University, Fuzhou, China
| | - D Li
- Department of Hepatobiliary Disease, Fuzhou General Hospital (Donfang Hospital), Xiamen University, Fuzhou, China.
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Age and Early Graft Function Relate With Risk-Benefit Ratio of Allogenic Islet Transplantation Under Antithymocyte Globulin-Mycophenolate Mofetil-Tacrolimus Immune Suppression. Transplantation 2017; 101:2218-2227. [DOI: 10.1097/tp.0000000000001543] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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43
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Ekdahl KN, Teramura Y, Hamad OA, Asif S, Duehrkop C, Fromell K, Gustafson E, Hong J, Kozarcanin H, Magnusson PU, Huber-Lang M, Garred P, Nilsson B. Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunol Rev 2017; 274:245-269. [PMID: 27782319 DOI: 10.1111/imr.12471] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.
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Affiliation(s)
- Kristina N Ekdahl
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.,Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
| | - Yuji Teramura
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.,Department of Bioengineering, The University of Tokyo, Tokyo, Japan
| | - Osama A Hamad
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Sana Asif
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Claudia Duehrkop
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Karin Fromell
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Elisabet Gustafson
- Department of Women's and Children's Health, Uppsala University Hospital, Uppsala, Sweden
| | - Jaan Hong
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Huda Kozarcanin
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Peetra U Magnusson
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Markus Huber-Lang
- Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University of Ulm, Ulm, Germany
| | - Peter Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Faculty of Health and Medical Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Bo Nilsson
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.
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Liu L, Tan J, Li B, Xie Q, Sun J, Pu H, Zhang L. Construction of functional pancreatic artificial islet tissue composed of fibroblast-modified polylactic- co-glycolic acid membrane and pancreatic stem cells. J Biomater Appl 2017; 32:362-372. [PMID: 28747082 DOI: 10.1177/0885328217722041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Objective To improve the biocompatibility between polylactic- co-glycolic acid membrane and pancreatic stem cells, rat fibroblasts were used to modify the polylactic- co-glycolic acid membrane. Meanwhile, we constructed artificial islet tissue by compound culturing the pancreatic stem cells and the fibroblast-modified polylactic- co-glycolic acid membrane and explored the function of artificial islets in diabetic nude mice. Methods Pancreatic stem cells were cultured on the fibroblast-modified polylactic- co-glycolic acid membrane in dulbecco's modified eagle medium containing activin-A, β-catenin, and exendin-4. The differentiated pancreatic stem cells combined with modified polylactic- co-glycolic acid membrane were implanted subcutaneously in diabetic nude mice. The function of artificial islet tissue was explored by detecting blood levels of glucose and insulin in diabetic nude mice. Moreover, the proliferation and differentiation of pancreatic stem cells on modified polylactic- co-glycolic acid membrane as well as the changes on the tissue structure of artificial islets were investigated by immunofluorescence and haematoxylin and eosin staining. Results The pancreatic stem cells differentiated into islet-like cells and secreted insulin when cultured on fibroblast-modified polylactic- co-glycolic acid membrane. Furthermore, when the artificial islet tissues were implanted into diabetic nude mice, the pancreatic stem cells combined with polylactic- co-glycolic acid membrane modified by fibroblasts proliferated, differentiated, and secreted insulin to reduce blood glucose levels in diabetic nude mice. Conclusion Pancreatic stem cells can be induced to differentiate into islet-like cells in vitro. In vivo, the artificial islet tissue can effectively regulate the blood glucose level in nude mice within a short period. However, as time increased, the structure of the artificial islets was destroyed due to the erosion of blood cells that resulted in the gradual loss of artificial islet function.
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Affiliation(s)
- Liping Liu
- 1 School of Chemical Engineering, Shanxi Datong University, Datong, Shanxi, China
| | - Jing Tan
- 2 Institute of Applied Biotechnology, Shanxi Datong University, Datong, Shanxi, China
| | - Baoyuan Li
- 2 Institute of Applied Biotechnology, Shanxi Datong University, Datong, Shanxi, China
| | - Qian Xie
- 3 School of Life Science, Shanxi Datong University, Datong, Shanxi, China
| | - Junwen Sun
- 3 School of Life Science, Shanxi Datong University, Datong, Shanxi, China
| | - Hongli Pu
- 3 School of Life Science, Shanxi Datong University, Datong, Shanxi, China
| | - Li Zhang
- 3 School of Life Science, Shanxi Datong University, Datong, Shanxi, China
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Cheng Y, Wang B, Li H, Zhao N, Liu Y. Mechanism for the Instant Blood-Mediated Inflammatory Reaction in Rat Islet Transplantation. Transplant Proc 2017; 49:1440-1443. [DOI: 10.1016/j.transproceed.2017.03.090] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 03/06/2017] [Accepted: 03/15/2017] [Indexed: 10/19/2022]
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Liu Z, Hu W, He T, Dai Y, Hara H, Bottino R, Cooper DKC, Cai Z, Mou L. Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future. Cell Transplant 2017; 26:925-947. [PMID: 28155815 PMCID: PMC5657750 DOI: 10.3727/096368917x694859] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 03/21/2017] [Indexed: 12/17/2022] Open
Abstract
Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased human donor pancreata limits progress. Islet xenotransplantation, using pigs as a source of islets, is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/inflammatory response to the porcine (pig) islets, which may take the form of rapid early graft rejection (the instant blood-mediated inflammatory reaction) or T-cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy. The results of pig-to-diabetic nonhuman primate islet xenotransplantation are steadily improving, with insulin independence being achieved for periods >1 year. An alternative approach is to isolate islets within a micro- or macroencapsulation device aimed at protecting them from the human recipient's immune response. Clinical trials using this approach are currently underway. This review focuses on the major aspects of pig-to-primate islet xenotransplantation and its potential for treatment of type 1 diabetes.
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Affiliation(s)
- Zhengzhao Liu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Wenbao Hu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Tian He
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Hidetaka Hara
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - David K. C. Cooper
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
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Park S, Lee DY. The anterior chamber of the eye as a site for pancreatic islet transplantation. J IND ENG CHEM 2017. [DOI: 10.1016/j.jiec.2017.02.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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MRI-sensitive contrast agent with anticoagulant activity for surface camouflage of transplanted pancreatic islets. Biomaterials 2017; 138:121-130. [PMID: 28558297 DOI: 10.1016/j.biomaterials.2017.05.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 05/08/2017] [Accepted: 05/21/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic islet implantation in the liver is a promising approach for diabetes therapy. However, 70% of the islet mass fails to be engrafted in the liver due to the instant blood-mediated inflammatory reactions (IBMIR) resulting from direct contact between islet cells and the bloodstream. To overcome this issue, direct monitoring is very important for establishing prognosis after islet cell therapy. Here we established a new type of MR contrast agent with anticoagulant activity via heparin-immobilized superparamagnetic iron oxide (HSPIO). The HSPIO was chemically conjugated onto islet surface ex vivo without damage of their viability and functionality. The conjugated HSPIO nanoparticles onto islet surface could attenuate IBMIR in vitro and in vivo. The HSPIO-conjugated islets could cure the blood glucose levels of diabetes animals after implantation. In addition, the HSPIO nanoparticles were well maintained on the transplanted islets for a long time during modulation of inflammation. Also, they allowed for stable visualization of the implanted islet cells for more than 150 days without reduction of the MRI signal. Furthermore, when HSPIO itself was intraportally injected, it was rapidly eliminated without accumulation in the liver, suggesting that HSPIO nanoparticles could only track the immobilized islet. Collectively, this HSPIO nanoparticle having MRI sensitivity and anticoagulant activity could be utilized for successful islet implantation.
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Abstract
PURPOSE OF REVIEW Diabetes is medical and social burden affecting millions around the world. Despite intensive therapy, insulin fails to maintain adequate glucose homeostasis and often results in episodes of hypoglycemic unawareness. Islet transplantation is a propitious replacement therapy, and incremental improvements in islet isolation and immunosuppressive drugs have made this procedure a feasible option. Shortage of donors, graft loss, and toxic immunosuppressive agents are few of many hurdles against making human allogenic islet transplantation a routine procedure. RECENT FINDINGS Xenografts-especially pig islets-offer a logical alternative source for islets. Current preclinical studies have revealed problems such as optimal islet source, zoonosis, and immune rejection. These issues are slowing clinical application. Genetically modified pigs, encapsulation devices, and new immune-suppressive regimens can confer graft protection. In addition, extrahepatic transplant sites are showing promising results. Notwithstanding few approved clinical human trials, and available data from non-human primates, recent reports indicate that porcine islets are closer to be the promising solution to cure diabetes.
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Affiliation(s)
- Bassem F Salama
- Department of Surgery, University of Alberta, 5.002 Li Ka Shing Bldg, 8602 112 Street, Edmonton, AB, T6G 2E1, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Gregory S Korbutt
- Department of Surgery, University of Alberta, 5.002 Li Ka Shing Bldg, 8602 112 Street, Edmonton, AB, T6G 2E1, Canada.
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
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50
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Delaune V, Berney T, Lacotte S, Toso C. Intraportal islet transplantation: the impact of the liver microenvironment. Transpl Int 2017; 30:227-238. [DOI: 10.1111/tri.12919] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 11/09/2016] [Accepted: 01/16/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Vaihere Delaune
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
| | - Thierry Berney
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
- Cell Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - Stéphanie Lacotte
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
| | - Christian Toso
- Hepatology and Transplantation Laboratory; Department of Surgery; Faculty of Medicine; University of Geneva; Geneva Switzerland
- Divisions of Abdominal and Transplantation Surgery; Department of Surgery; Geneva University Hospitals; Geneva Switzerland
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