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Piemonti L, Citro A, Tomajer V, Partelli S, Caldara R. Pig Xenotransplantation in Beta Cell Replacement: Addressing Challenges and Harnessing Potential for Type 1 Diabetes Therapy. Transpl Int 2024; 37:13122. [PMID: 39512630 PMCID: PMC11540633 DOI: 10.3389/ti.2024.13122] [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: 04/11/2024] [Accepted: 10/14/2024] [Indexed: 11/15/2024]
Abstract
This opinion paper evaluates the potential of porcine islets as a promising alternative in beta cell replacement therapy for Type 1 Diabetes (T1D), juxtaposed with the current limitations of human donor islets. It analyzes the compatibility of pig islets with human glucose metabolism, their prospects as a limitless and high-quality source of beta cells, and the unique immunogenic challenges they present in xenotransplantation. Additionally, the paper discusses the regulatory and ethical considerations pertinent to the use of porcine islets. By synthesizing current research and expert perspectives, the paper highlights both the opportunities and significant barriers that need addressing to advance pig islets as a viable therapeutic option. The findings advocate for a balanced and forward-looking approach to the integration of pig islets in T1D treatment, underscoring the need for continued research and dialogue in this evolving field.
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Affiliation(s)
- Lorenzo Piemonti
- Clinic Unit of Regenerative Medicine and Organ Transplants and Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
- Diabetes Research Institute, Università Vita-Salute San Raffaele, Milan, Italy
| | - Antonio Citro
- Clinic Unit of Regenerative Medicine and Organ Transplants and Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
| | - Valentina Tomajer
- Pancreatic Surgery, Pancreas Translational and Clinical Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
| | - Stefano Partelli
- Diabetes Research Institute, Università Vita-Salute San Raffaele, Milan, Italy
- Pancreatic Surgery, Pancreas Translational and Clinical Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
| | - Rossana Caldara
- Clinic Unit of Regenerative Medicine and Organ Transplants and Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
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Opara A, Canning P, Alwan A, Opara EC. Challenges and Perspectives for Future Considerations in the Bioengineering of a Bioartificial Pancreas. Ann Biomed Eng 2024; 52:1795-1803. [PMID: 36913086 DOI: 10.1007/s10439-023-03180-7] [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: 10/21/2022] [Accepted: 02/25/2023] [Indexed: 03/14/2023]
Abstract
There is an unrelenting interest in the development of a reliable bioartificial pancreas construct since the first description of this technology of encapsulated islets by Lim and Sun in 1980 because it promised to be a curative treatment for Type 1 Diabetes Mellitus (T1DM). Despite the promise of the concept of encapsulated islets, there are still some challenges that impede the full realization of the clinical potential of the technology. In this review, we will first present the justification for continued research and development of this technology. Next, we will review key barriers that impede progress in this field and discuss strategies that can be used to design a reliable construct capable of effective long-term performance after transplantation in diabetic patients. Finally, we will share our perspectives on areas of additional work for future research and development of the technology.
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Affiliation(s)
- Amoge Opara
- Diabetes Section, Biologics Delivery Technologies, Reno, NV, 89502, USA
| | - Priyadarshini Canning
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Abdelrahman Alwan
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Emmanuel C Opara
- Diabetes Section, Biologics Delivery Technologies, Reno, NV, 89502, USA.
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences (SBES), Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
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3
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Cooper DKC, Mou L, Bottino R. A brief review of the current status of pig islet xenotransplantation. Front Immunol 2024; 15:1366530. [PMID: 38464515 PMCID: PMC10920266 DOI: 10.3389/fimmu.2024.1366530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 02/07/2024] [Indexed: 03/12/2024] Open
Abstract
An estimated 1.5 million Americans suffer from Type I diabetes mellitus, and its incidence is increasing worldwide. Islet allotransplantation offers a treatment, but the availability of deceased human donor pancreases is limited. The transplantation of islets from gene-edited pigs, if successful, would resolve this problem. Pigs are now available in which the expression of the three known xenoantigens against which humans have natural (preformed) antibodies has been deleted, and in which several human 'protective' genes have been introduced. The transplantation of neonatal pig islets has some advantages over that of adult pig islets. Transplantation into the portal vein of the recipient results in loss of many islets from the instant blood-mediated inflammatory reaction (IBMIR) and so the search for an alternative site continues. The adaptive immune response can be largely suppressed by an immunosuppressive regimen based on blockade of the CD40/CD154 T cell co-stimulation pathway, whereas conventional therapy (e.g., based on tacrolimus) is less successful. We suggest that, despite the need for effective immunosuppressive therapy, the transplantation of 'free' islets will prove more successful than that of encapsulated islets. There are data to suggest that, in the absence of rejection, the function of pig islets, though less efficient than human islets, will be sufficient to maintain normoglycemia in diabetic recipients. Pig islets transplanted into immunosuppressed nonhuman primates have maintained normoglycemia for periods extending more than two years, illustrating the potential of this novel form of therapy.
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Affiliation(s)
- David K. C. Cooper
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
| | - Lisha Mou
- Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- MetaLife Center, Shenzhen Institute of Translational Medicine, Shenzhen, Guangdong, China
| | - Rita Bottino
- Imagine Islet Center, Imagine Pharma, Pittsburgh, PA, United States
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Affiliation(s)
- Jay A Fishman
- From the Transplant and Immunocompromised Host Program, Infectious Disease Division and Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston
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5
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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: 65] [Impact Index Per Article: 21.7] [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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6
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Pignatelli C, Campo F, Neroni A, Piemonti L, Citro A. Bioengineering the Vascularized Endocrine Pancreas: A Fine-Tuned Interplay Between Vascularization, Extracellular-Matrix-Based Scaffold Architecture, and Insulin-Producing Cells. Transpl Int 2022; 35:10555. [PMID: 36090775 PMCID: PMC9452644 DOI: 10.3389/ti.2022.10555] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 08/11/2022] [Indexed: 11/23/2022]
Abstract
Intrahepatic islet transplantation is a promising β-cell replacement strategy for the treatment of type 1 diabetes. Instant blood-mediated inflammatory reactions, acute inflammatory storm, and graft revascularization delay limit islet engraftment in the peri-transplant phase, hampering the success rate of the procedure. Growing evidence has demonstrated that islet engraftment efficiency may take advantage of several bioengineering approaches aimed to recreate both vascular and endocrine compartments either ex vivo or in vivo. To this end, endocrine pancreas bioengineering is an emerging field in β-cell replacement, which might provide endocrine cells with all the building blocks (vascularization, ECM composition, or micro/macro-architecture) useful for their successful engraftment and function in vivo. Studies on reshaping either the endocrine cellular composition or the islet microenvironment have been largely performed, focusing on a single building block element, without, however, grasping that their synergistic effect is indispensable for correct endocrine function. Herein, the review focuses on the minimum building blocks that an ideal vascularized endocrine scaffold should have to resemble the endocrine niche architecture, composition, and function to foster functional connections between the vascular and endocrine compartments. Additionally, this review highlights the possibility of designing bioengineered scaffolds integrating alternative endocrine sources to overcome donor organ shortages and the possibility of combining novel immune-preserving strategies for long-term graft function.
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Affiliation(s)
- Cataldo Pignatelli
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Campo
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Alessia Neroni
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Huang J, China Organ Transplantation Development Foundation. Expert consensus on clinical trials of human xenotransplantation in China. HEALTH CARE SCIENCE 2022; 1:7-10. [PMID: 38939355 PMCID: PMC11080631 DOI: 10.1002/hcs2.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/10/2022] [Accepted: 06/15/2022] [Indexed: 06/29/2024]
Abstract
The history of xenotransplantation started in the 19th century. After a few decades of investigation, significant breakthroughs and preclinical milestones have been achieved worldwide. With the recent transplantation of genetically modified porcine kidneys and heart into humans, these ground-breaking achievements have attracted great attention worldwide, in the hope that xenotransplantation might alleviate or even solve the problem of organ shortage. On January 20, 2022, the China Organ Transplantation Development Foundation convened a symposium on "The History, Current Situation and Future of Human Xenotransplantation Clinical Trials," where ways to promote the ethical and sustainable development of xenotransplantation in China were discussed among the participating experts. A formal consensus was reached as the product of the symposium, outlining the expert opinions on scientific, regulatory, and ethical issues of clinical trials of xenotransplantation in China.
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Affiliation(s)
- Jiefu Huang
- China Organ Transplantation Development FoundationBeijingChina
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Viability and Functionality of Neonatal Porcine Islet-like Cell Clusters Bioprinted in Alginate-Based Bioinks. Biomedicines 2022; 10:biomedicines10061420. [PMID: 35740440 PMCID: PMC9220255 DOI: 10.3390/biomedicines10061420] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 11/17/2022] Open
Abstract
The transplantation of pancreatic islets can prevent severe long-term complications in diabetes mellitus type 1 patients. With respect to a shortage of donor organs, the transplantation of xenogeneic islets is highly attractive. To avoid rejection, islets can be encapsulated in immuno-protective hydrogel-macrocapsules, whereby 3D bioprinted structures with macropores allow for a high surface-to-volume ratio and reduced diffusion distances. In the present study, we applied 3D bioprinting to encapsulate the potentially clinically applicable neonatal porcine islet-like cell clusters (NICC) in alginate-methylcellulose. The material was additionally supplemented with bovine serum albumin or the human blood plasma derivatives platelet lysate and fresh frozen plasma. NICC were analysed for viability, proliferation, the presence of hormones, and the release of insulin in reaction to glucose stimulation. Bioprinted NICC are homogeneously distributed, remain morphologically intact, and show a comparable viability and proliferation to control NICC. The number of insulin-positive cells is comparable between the groups and over time. The amount of insulin release increases over time and is released in response to glucose stimulation over 4 weeks. In summary, we show the successful bioprinting of NICC and could demonstrate functionality over the long-term in vitro. Supplementation resulted in a trend for higher viability, but no additional benefit on functionality was observed.
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Huang HH, Stillman TJ, Branham LA, Williams SC. The Effects of Photobiomodulation Therapy on Porcine Islet Insulin Secretion. Photobiomodul Photomed Laser Surg 2022; 40:395-401. [DOI: 10.1089/photob.2022.0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Han-Hung Huang
- Department of Physical Therapy, Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| | - Tori J. Stillman
- Department of Agriculture, and Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| | - Loree A. Branham
- Department of Agriculture, and Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| | - Scott C. Williams
- Department of Physics and Geosciences, Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
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10
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Scheibner K, Lickert H. Awaking sleeping islets for a cure of diabetes. MED 2022; 3:279-280. [DOI: 10.1016/j.medj.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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11
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Denner J. Porcine Endogenous Retroviruses and Xenotransplantation, 2021. Viruses 2021; 13:v13112156. [PMID: 34834962 PMCID: PMC8625113 DOI: 10.3390/v13112156] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/06/2021] [Accepted: 10/20/2021] [Indexed: 12/25/2022] Open
Abstract
Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for xenotransplantation, the transplantation of pig cells, tissues, or organ to humans in order to alleviate the shortage of human donor organs. Up to 2021, a huge body of knowledge about PERVs has been accumulated regarding their biology, including replication, recombination, origin, host range, and immunosuppressive properties. Until now, no PERV transmission has been observed in clinical trials transplanting pig islet cells into diabetic humans, in preclinical trials transplanting pig cells and organs into nonhuman primates with remarkable long survival times of the transplant, and in infection experiments with several animal species. Nevertheless, in order to prevent virus transmission to the recipient, numerous strategies have been developed, including selection of PERV-C-free animals, RNA interference, antiviral drugs, vaccination, and genome editing. Furthermore, at present there are no more experimental approaches to evaluate the full risk until we move to the clinic.
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Affiliation(s)
- Joachim Denner
- Department of Veterinary Medicine, Institute of Virology, Free University Berlin, 14163 Berlin, Germany
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12
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Krentz NAJ, Shea LD, Huising MO, Shaw JAM. Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering. Lancet Diabetes Endocrinol 2021; 9:708-724. [PMID: 34480875 PMCID: PMC10881068 DOI: 10.1016/s2213-8587(21)00170-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 02/09/2023]
Abstract
Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.
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Affiliation(s)
- Nicole A J Krentz
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Lonnie D Shea
- Departments of Biomedical Engineering, Chemical Engineering, and Surgery, College of Engineering and School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - James A M Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
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Kemter E, Müller A, Neukam M, Ivanova A, Klymiuk N, Renner S, Yang K, Broichhagen J, Kurome M, Zakhartchenko V, Kessler B, Knoch KP, Bickle M, Ludwig B, Johnsson K, Lickert H, Kurth T, Wolf E, Solimena M. Sequential in vivo labeling of insulin secretory granule pools in INS- SNAP transgenic pigs. Proc Natl Acad Sci U S A 2021; 118:e2107665118. [PMID: 34508004 PMCID: PMC8449372 DOI: 10.1073/pnas.2107665118] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 12/16/2022] Open
Abstract
β cells produce, store, and secrete insulin upon elevated blood glucose levels. Insulin secretion is a highly regulated process. The probability for insulin secretory granules to undergo fusion with the plasma membrane or being degraded is correlated with their age. However, the molecular features and stimuli connected to this behavior have not yet been fully understood. Furthermore, our understanding of β cell function is mostly derived from studies of ex vivo isolated islets in rodent models. To overcome this translational gap and study insulin secretory granule turnover in vivo, we have generated a transgenic pig model with the SNAP-tag fused to insulin. We demonstrate the correct targeting and processing of the tagged insulin and normal glycemic control of the pig model. Furthermore, we show specific single- and dual-color granular labeling of in vivo-labeled pig pancreas. This model may provide unprecedented insights into the in vivo insulin secretory granule behavior in an animal close to humans.
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Affiliation(s)
- Elisabeth Kemter
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Andreas Müller
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Martin Neukam
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Anna Ivanova
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Nikolai Klymiuk
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
| | - Simone Renner
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Kaiyuan Yang
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Johannes Broichhagen
- Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany
- Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany
| | - Mayuko Kurome
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
| | - Valeri Zakhartchenko
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
| | - Barbara Kessler
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
| | - Klaus-Peter Knoch
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Marc Bickle
- Technology Development Studio (TDS), Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Barbara Ludwig
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Department of Medicine III, University Hospital Carl Gustav Carus, 01307 Dresden, Germany
| | - Kai Johnsson
- Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany
| | - Heiko Lickert
- German Center for Diabetes Research, 85764 Neuherberg, Germany
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Thomas Kurth
- Center for Molecular and Cellular Bioengineering Technology Platform, Technische Universität Dresden, 01307 Dresden, Germany
| | - Eckhard Wolf
- Chair for Molecular Animal Breeding and Biotechnology Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany;
- Center for Innovative Medical Models, Ludwig Maximilian University of Munich, 81377 Munich, Germany
- German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Michele Solimena
- German Center for Diabetes Research, 85764 Neuherberg, Germany;
- Molecular Diabetology, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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14
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Ryu JH, Ko HJ, Shim JR, Lee TB, Yang KH, Kim T, Choi BH. Technical factors that minimize the occurrence of early graft failure in pancreas transplantation. Clin Transplant 2021; 35:e14455. [PMID: 34390276 DOI: 10.1111/ctr.14455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 11/28/2022]
Abstract
Pancreatic transplantation is the only treatment for insulin-dependent diabetes resulting in long-term euglycemia without exogenous insulin. However, pancreatic transplantation has become debatable following the improvements in the results of islet transplantation and artificial pancreas. Therefore, surgeons who perform pancreas transplants require the best surgical technique that can minimize technical failure. We aimed to report our experiences with pancreatic transplantations. We transplanted 65 pancreatic grafts between 2015 and 2020. Except for one death due to hypoxic brain damage after surgery, no postoperative technical failure was observed. We usually perform duodeno-duodenal anastomosis using the transperitoneal approach, with retrocolic placement of the graft pancreas. There was no leakage from the duodenum even after immunologic graft failure. To prevent venous thrombosis, which is the most common cause of technical failure, we used the inferior vena cava for anastomosis and added graft venoplasty with a patch of donor vena cava or aortic interposition graft to the bench procedure; subsequently, there were no cases of technical failure due to thrombosis post-transplantation. Therefore, the 1-year graft survival (insulin-free) rate was more than 95%. The improving the surgical technique will maintain pancreatic transplantation as the best treatment for insulin-dependent diabetes. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Je Ho Ryu
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea.,Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Hyo Jung Ko
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Jae Ryong Shim
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Tae Beom Lee
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Kwang Ho Yang
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Taeun Kim
- Department of Radiology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Byung Hyun Choi
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea.,Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea
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15
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Soetedjo AAP, Lee JM, Lau HH, Goh GL, An J, Koh Y, Yeong WY, Teo AKK. Tissue engineering and 3D printing of bioartificial pancreas for regenerative medicine in diabetes. Trends Endocrinol Metab 2021; 32:609-622. [PMID: 34154916 DOI: 10.1016/j.tem.2021.05.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/08/2023]
Abstract
Diabetes is a severe chronic disease worldwide. In various types of diabetes, the pancreatic beta cells fail to secrete sufficient insulin, at some point, to regulate blood glucose levels. Therefore, the replacement of dysfunctional pancreas, islets of Langerhans, or even the insulin-secreting beta cells facilitates physiological regulation of blood glucose levels. However, the current lack of sufficient donor human islets for cell replacement therapy precludes a routine and absolute cure for most of the existing diabetes cases globally. It is envisioned that tissue engineering of a bioartificial pancreas will revolutionize regenerative medicine and the treatment of diabetes. In this review, we discuss the anatomy and physiology of the pancreas, and identify the clinical considerations for engineering a bioartificial pancreas. Subsequently, we dissect the bioengineering problem based on the design of the device, the biomaterial used, and the cells involved. Last but not least, we highlight current tissue engineering challenges and explore potential directions for future work.
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Affiliation(s)
- Andreas Alvin Purnomo Soetedjo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore
| | - Jia Min Lee
- School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Hwee Hui Lau
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore
| | - Guo Liang Goh
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Jia An
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Yexin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Wai Yee Yeong
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; Department of Biochemistry and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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16
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Infectivity assessment of porcine endogenous retrovirus using high-throughput sequencing technologies. Biologicals 2021; 71:1-8. [PMID: 34039532 DOI: 10.1016/j.biologicals.2021.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/06/2021] [Accepted: 05/10/2021] [Indexed: 11/20/2022] Open
Abstract
Xenogenic cell-based therapeutic products are expected to alleviate the chronic shortage of human donor organs. For example, porcine islet cell products are currently under development for the treatment of human diabetes. As porcine cells possess endogenous retrovirus (PERV), which can replicate in human cells in vitro, the potential transmission of PERV has raised concerns in the case of products that use living pig cells as raw materials. Although several PERV sequences exist in the porcine genome, not all have the ability to infect human cells. Therefore, polymerase chain reaction analysis, which amplifies a portion of the target gene, may not accurately assess the infection risk. Here, we determined porcine genome sequences and evaluated the infectivity of PERVs using high-throughput sequencing technologies. RNA sequencing was performed on both PERV-infected human cells and porcine cells, and reads mapped to PERV sequences were examined. The normalized number of the reads mapped to PERV regions was able to predict the infectivity of PERVs, indicating that it would be useful for evaluation of the PERV infection risk prior to transplantation of porcine products.
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17
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Akbarian M. Insulin therapy; a valuable legacy and its future perspective. Int J Biol Macromol 2021; 181:1224-1230. [PMID: 33989689 DOI: 10.1016/j.ijbiomac.2021.05.052] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/21/2021] [Accepted: 05/06/2021] [Indexed: 11/30/2022]
Abstract
Proteins and peptides are widely used in various areas including pharmaceutical, health, food, textile and biofuel industries. At present, pharmaceutical proteins and peptides have attracted the attention of many researchers. These types of drugs are superior to chemical drugs in many ways so that every year the number of drugs with a protein or peptide moiety is increasing. Due to high performance and low side effects, the demand for these drugs has increased year by year. The beginning of the protein and peptide drug industry dates back to 1982 with the introduction of the protein hormone insulin into the field of treatment. From this year onwards, a new number of protein and peptide drugs have entered the field of treatment every year. In this article, we focus on human therapeutic insulin. First, the history of the hormone will be introduced, then-current methods for insulin therapy will be discussed and finally, the treatments by this hormone in the future will be pointed. Reading this article would be very helpful for nano researchers, biochemists, organic chemists, material scientists and other people who are interested in soft and hard matters interfaces.
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Affiliation(s)
- Mohsen Akbarian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan..
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18
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Nagaya M, Hasegawa K, Uchikura A, Nakano K, Watanabe M, Umeyama K, Matsunari H, Osafune K, Kobayashi E, Nakauchi H, Nagashima H. Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes. World J Diabetes 2021; 12:306-330. [PMID: 33889282 PMCID: PMC8040081 DOI: 10.4239/wjd.v12.i4.306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017. The incidence and prevalence of diabetes is predicted to increase. To alleviate this potentially severe situation, safer and more effective therapeutics are urgently required. Mice have long been the mainstay as preclinical models for basic research on diabetes, although they are not ideally suited for translating basic knowledge into clinical applications. To validate and optimize novel therapeutics for safe application in humans, an appropriate large animal model is needed. Large animals, especially pigs, are well suited for biomedical research and share many similarities with humans, including body size, anatomical features, physiology, and pathophysiology. Moreover, pigs already play an important role in translational studies, including clinical trials for xenotransplantation. Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals, including porcine models of diabetes. This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
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Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Department of Immunology, St. Marianna University School of Medicine, Kawasaki 261-8511, Kanagawa, Japan
| | - Koki Hasegawa
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Ayuko Uchikura
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Kyoto, Japan
| | - Eiji Kobayashi
- Department of Organ Fabrication, Keio University School of Medicine, Shinjuku 160-8582, Tokyo, Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, United States
- Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Minato 108-8639, Tokyo, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
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19
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Affiliation(s)
- Konrad Fischer
- Chair of Livestock Biotechnology, Technical University of Munich, Freising, Germany
| | - Angelika Schnieke
- Chair of Livestock Biotechnology, Technical University of Munich, Freising, Germany.
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20
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Carvalho-Oliveira M, Valdivia E, Blasczyk R, Figueiredo C. Immunogenetics of xenotransplantation. Int J Immunogenet 2021; 48:120-134. [PMID: 33410582 DOI: 10.1111/iji.12526] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/06/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023]
Abstract
Xenotransplantation may become the highly desired solution to close the gap between the availability of donated organs and number of patients on the waiting list. In recent years, enormous progress has been made in the development of genetically engineered donor pigs. The introduced genetic modifications showed to be efficient in prolonging xenograft survival. In this review, we focus on the type of immune responses that may target xeno-organs after transplantation and promising immunogenetic modifications that show a beneficial effect in ameliorating or eliminating harmful xenogeneic immune responses. Increasing histocompatibility of xenografts by eliminating genetic discrepancies between species will pave their way into clinical application.
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Affiliation(s)
- Marco Carvalho-Oliveira
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany.,TRR127 - Biology of Xenogeneic Cell and Organ Transplantation - from bench to bedside, Hannover, Germany
| | - Emilio Valdivia
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany.,TRR127 - Biology of Xenogeneic Cell and Organ Transplantation - from bench to bedside, Hannover, Germany
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21
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Yoon CH, Choi HJ, Kim MK. Corneal xenotransplantation: Where are we standing? Prog Retin Eye Res 2021; 80:100876. [PMID: 32755676 PMCID: PMC7396149 DOI: 10.1016/j.preteyeres.2020.100876] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/23/2020] [Accepted: 06/04/2020] [Indexed: 02/08/2023]
Abstract
The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed, current progress in genetically engineered (GE) pigs, the introduction of gene-editing technology by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, and advanced immunosuppressants have made xenotransplantation a possible option for a human trial. Porcine corneal xenotransplantation is considered applicable because the eye is regarded as an immune-privileged site. Furthermore, recent non-human primate studies have shown long-term survival of porcine xenotransplants in keratoplasty. Herein, corneal immune privilege is briefly introduced, and xenogeneic reactions are compared with allogeneic reactions in corneal transplantation. This review describes the current knowledge on special issues of xenotransplantation, xenogeneic rejection mechanisms, current immunosuppressive regimens of corneal xenotransplantation, preclinical efficacy and safety data of corneal xenotransplantation, and updates of the regulatory framework to conduct a clinical trial on corneal xenotransplantation. We also discuss barriers that might prevent xenotransplantation from becoming common practice, such as ethical dilemmas, public concerns on xenotransplantation, and the possible risk of xenozoonosis. Given that the legal definition of decellularized porcine cornea (DPC) lies somewhere between a medical device and a xenotransplant, the preclinical efficacy and clinical trial data using DPC are included. The review finally provides perspectives on the current standpoint of corneal xenotransplantation in the fields of regenerative medicine.
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Affiliation(s)
- Chang Ho Yoon
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea
| | - Hyuk Jin Choi
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea; Department of Ophthalmology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Mee Kum Kim
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, Republic of Korea.
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22
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Kono K, Kataoka K, Yuan Y, Yusa K, Uchida K, Sato Y. A highly sensitive method for the detection of recombinant PERV-A/C env RNA using next generation sequencing technologies. Sci Rep 2020; 10:21935. [PMID: 33318655 PMCID: PMC7736861 DOI: 10.1038/s41598-020-78890-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 11/30/2020] [Indexed: 12/27/2022] Open
Abstract
Several xenogenic cell-based therapeutic products are currently under development around the world for the treatment of human diseases. Porcine islet cell products for treating human diabetes are a typical example. Since porcine cells possess endogenous retrovirus (PERV), which can replicate in human cells in vitro, the potential transmission of PERV has raised concerns in the development of these products. Four subgroups of infectious PERV have been identified, namely PERV-A, -B, -C, and recombinant PERV-A/C. Among them, PERV-A/C shows a high titre and there was a paper reported that an incidence of PERV-A/C viremia was increased in diseased pigs; thus, it would be important to monitor the emergence of PERV-A/C after transplantation of porcine products. In this study, we developed a highly sensitive method for the detection of PERV-A/C using next generation sequencing (NGS) technologies. A model PERV-C spiked with various doses of PERV-A/C were amplified by RT-PCR and the amplicons were analysed by NGS. We found that the NGS analysis allowed the detection of PERV-A/C at the abundance ratios of 1% and 0.1% with true positive rates of 100% and 57%, respectively, indicating that it would be useful for the rapid detection of PERV-A/C emergence after transplantation of porcine products.
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Affiliation(s)
- Ken Kono
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Kiyoko Kataoka
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan
| | - Yuzhe Yuan
- Graduate School of Science, Technology and Innovation, Kobe University, Hyogo, Japan
| | - Keisuke Yusa
- Graduate School of Science, Technology and Innovation, Kobe University, Hyogo, Japan
| | - Kazuhisa Uchida
- Graduate School of Science, Technology and Innovation, Kobe University, Hyogo, Japan
| | - Yoji Sato
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki Ward, Kawasaki City, Kanagawa, 210-9501, Japan. .,Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. .,Department of Cellular and Gene Therapy Products, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
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23
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Welch NG, Winkler DA, Thissen H. Antifibrotic strategies for medical devices. Adv Drug Deliv Rev 2020; 167:109-120. [PMID: 32553685 DOI: 10.1016/j.addr.2020.06.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022]
Abstract
A broad range of medical devices initiate an immune reaction known as the foreign body response (FBR) upon implantation. Here, collagen deposition at the surface of the implant occurs as a result of the FBR, ultimately leading to fibrous encapsulation and, in many cases, reduced function or failure of the device. Despite significant efforts, the prevention of fibrotic encapsulation has not been realized at this point in time. However, many next-generation medical technologies including cellular therapies, sensors and devices depend on the ability to modulate and control the FBR. For these technologies to become viable, significant advances must be made in understanding the underlying mechanism of this response as well as in the methods modulating this response. In this review, we highlight recent advances in the development of materials and coatings providing a reduced FBR and emphasize key characteristics of high-performing approaches. We also provide a detailed overview of the state-of-the-art in strategies relying on controlled drug release, the surface display of bioactive signals, materials-based approaches, and combinations of these approaches. Finally, we offer perspectives on future directions in this field.
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24
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Arroyave F, Montaño D, Lizcano F. Diabetes Mellitus Is a Chronic Disease that Can Benefit from Therapy with Induced Pluripotent Stem Cells. Int J Mol Sci 2020; 21:ijms21228685. [PMID: 33217903 PMCID: PMC7698772 DOI: 10.3390/ijms21228685] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/20/2020] [Accepted: 10/31/2020] [Indexed: 12/17/2022] Open
Abstract
Diabetes mellitus (DM) is one of the main causes of morbidity and mortality, with an increasing incidence worldwide. The impact of DM on public health in developing countries has triggered alarm due to the exaggerated costs of the treatment and monitoring of patients with this disease. Considerable efforts have been made to try to prevent the onset and reduce the complications of DM. However, because insulin-producing pancreatic β-cells progressively deteriorate, many people must receive insulin through subcutaneous injection. Additionally, current therapies do not have consistent results regarding the prevention of chronic complications. Leveraging the approval of real-time continuous glucose monitors and sophisticated algorithms that partially automate insulin infusion pumps has improved glycemic control, decreasing the burden of diabetes management. However, these advances are facing physiologic barriers. New findings in molecular and cellular biology have produced an extraordinary advancement in tissue development for the treatment of DM. Obtaining pancreatic β-cells from somatic cells is a great resource that currently exists for patients with DM. Although this therapeutic option has great prospects for patients, some challenges remain for this therapeutic plan to be used clinically. The purpose of this review is to describe the new techniques in cell biology and regenerative medicine as possible treatments for DM. In particular, this review highlights the origin of induced pluripotent cells (iPSCs) and how they have begun to emerge as a regenerative treatment that may mitigate the pathology of this disease.
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Affiliation(s)
- Felipe Arroyave
- Doctoral Program in Biosciences, Universidad de La Sabana, Chía 250008, CU, Colombia;
| | - Diana Montaño
- Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chía 250008, CU, Colombia;
| | - Fernando Lizcano
- Doctoral Program in Biosciences, Universidad de La Sabana, Chía 250008, CU, Colombia;
- Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chía 250008, CU, Colombia;
- Correspondence: ; Tel.: +57-3144120052 or +57-18615555 (ext. 23906)
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25
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Kupikowska-Stobba B, Lewińska D. Polymer microcapsules and microbeads as cell carriers for in vivo biomedical applications. Biomater Sci 2020; 8:1536-1574. [PMID: 32110789 DOI: 10.1039/c9bm01337g] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Polymer microcarriers are being extensively explored as cell delivery vehicles in cell-based therapies and hybrid tissue and organ engineering. Spherical microcarriers are of particular interest due to easy fabrication and injectability. They include microbeads, composed of a porous matrix, and microcapsules, where matrix core is additionally covered with a semipermeable membrane. Microcarriers provide cell containment at implantation site and protect the cells from host immunoresponse, degradation and shear stress. Immobilized cells may be genetically altered to release a specific therapeutic product directly at the target site, eliminating side effects of systemic therapies. Cell microcarriers need to fulfil a number of extremely high standards regarding their biocompatibility, cytocompatibility, immunoisolating capacity, transport, mechanical and chemical properties. To obtain cell microcarriers of specified parameters, a wide variety of polymers, both natural and synthetic, and immobilization methods can be applied. Yet so far, only a few approaches based on cell-laden microcarriers have reached clinical trials. The main issue that still impedes progress of these systems towards clinical application is limited cell survival in vivo. Herein, we review polymer biomaterials and methods used for fabrication of cell microcarriers for in vivo biomedical applications. We describe their key limitations and modifications aiming at improvement of microcarrier in vivo performance. We also present the main applications of polymer cell microcarriers in regenerative medicine, pancreatic islet and hepatocyte transplantation and in the treatment of cancer. Lastly, we outline the main challenges in cell microimmobilization for biomedical purposes, the strategies to overcome these issues and potential future improvements in this area.
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Affiliation(s)
- Barbara Kupikowska-Stobba
- Laboratory of Electrostatic Methods of Bioencapsulation, Department of Biomaterials and Biotechnological Systems, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Trojdena 4, 02-109 Warsaw, Poland.
| | - Dorota Lewińska
- Laboratory of Electrostatic Methods of Bioencapsulation, Department of Biomaterials and Biotechnological Systems, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Trojdena 4, 02-109 Warsaw, Poland.
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26
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The resurgent landscape of xenotransplantation of pig organs in nonhuman primates. SCIENCE CHINA-LIFE SCIENCES 2020; 64:697-708. [PMID: 32975720 DOI: 10.1007/s11427-019-1806-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 08/27/2020] [Indexed: 12/14/2022]
Abstract
Organ shortage is a major bottleneck in allotransplantation and causes many wait-listed patients to die or become too sick for transplantation. Genetically engineered pigs have been discussed as a potential alternative to allogeneic donor organs. Although xenotransplantation of pig-derived organs in nonhuman primates (NHPs) has shown sequential advances in recent years, there are still underlying problems that need to be completely addressed before clinical applications, including (i) acute humoral xenograft rejection; (ii) acute cellular rejection; (iii) dysregulation of coagulation and inflammation; (iv) physiological incompatibility; and (v) cross-species infection. Moreover, various genetic modifications to the pig donor need to be fully characterized, with the aim of identifying the ideal transgene combination for upcoming clinical trials. In addition, suitable pretransplant screening methods need to be confirmed for optimal donor-recipient matching, ensuring a good outcome from xenotransplantation. Herein, we summarize the understanding of organ xenotransplantation in pigs-to-NHPs and highlight the current status and recent progress in extending the survival time of pig xenografts and recipients. We also discuss practical strategies for overcoming the obstacles to xenotransplantation mentioned above to further advance transplantation of pig organs in the clinic.
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27
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Zettler S, Renner S, Kemter E, Hinrichs A, Klymiuk N, Backman M, Riedel EO, Mueller C, Streckel E, Braun-Reichhart C, Martins AS, Kurome M, Keßler B, Zakhartchenko V, Flenkenthaler F, Arnold GJ, Fröhlich T, Blum H, Blutke A, Wanke R, Wolf E. A decade of experience with genetically tailored pig models for diabetes and metabolic research. Anim Reprod 2020; 17:e20200064. [PMID: 33029223 PMCID: PMC7534555 DOI: 10.1590/1984-3143-ar2020-0064] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023] Open
Abstract
The global prevalence of diabetes mellitus and other metabolic diseases is rapidly increasing. Animal models play pivotal roles in unravelling disease mechanisms and developing and testing therapeutic strategies. Rodents are the most widely used animal models but may have limitations in their resemblance to human disease mechanisms and phenotypes. Findings in rodent models are consequently often difficult to extrapolate to human clinical trials. To overcome this ‘translational gap’, we and other groups are developing porcine disease models. Pigs share many anatomical and physiological traits with humans and thus hold great promise as translational animal models. Importantly, the toolbox for genetic engineering of pigs is rapidly expanding. Human disease mechanisms and targets can therefore be reproduced in pigs on a molecular level, resulting in precise and predictive porcine (PPP) models. In this short review, we summarize our work on the development of genetically (pre)diabetic pig models and how they have been used to study disease mechanisms and test therapeutic strategies. This includes the generation of reporter pigs for studying beta-cell maturation and physiology. Furthermore, genetically engineered pigs are promising donors of pancreatic islets for xenotransplantation. In summary, genetically tailored pig models have become an important link in the chain of translational diabetes and metabolic research.
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Affiliation(s)
- Silja Zettler
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Simone Renner
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Elisabeth Kemter
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany.,German Center for Diabetes Research, Neuherberg, Germany
| | - Arne Hinrichs
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Nikolai Klymiuk
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Mattias Backman
- Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Munich
| | | | - Christiane Mueller
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Elisabeth Streckel
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Christina Braun-Reichhart
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Ana Sofia Martins
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Mayuko Kurome
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Barbara Keßler
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | - Valeri Zakhartchenko
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany
| | | | - Georg Josef Arnold
- Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Munich
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Munich
| | - Helmut Blum
- Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Munich
| | - Andreas Blutke
- Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Rüdiger Wanke
- Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, LMU Munich, Munich, Germany
| | - Eckhard Wolf
- Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany.,Center for Innovative Medical Models, Department of Veterinary Sciences, LMU Munich, Oberschleißheim, Germany.,German Center for Diabetes Research, Neuherberg, Germany.,Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Munich
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Cui Y, Yamamoto T, Raza SS, Morsi M, Nguyen HQ, Ayares D, Cooper DK, Hara H. Evidence for GTKO/β4GalNT2KO Pigs as the Preferred Organ-source for Old World Nonhuman Primates as a Preclinical Model of Xenotransplantation. Transplant Direct 2020; 6:e590. [PMID: 32766438 PMCID: PMC7382549 DOI: 10.1097/txd.0000000000001038] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Triple-knockout (TKO) pigs (in which expression of the 3 known pig carbohydrate xenoantigens has been deleted) are likely to be an optimal source of organs for transplantation into human recipients, many of whom do not have natural antibodies against TKO pig cells. However, old world monkeys, for example, baboons, have natural antibodies directed to TKO cells (to a "fourth" xenoantigen that is exposed after TKO). METHODS We measured (1) anti-pig IgM/IgG binding, and (2) complement-dependent cytotoxicity (CDC), by flow cytometry to α1,3-galactosyltransfearse gene-knockout (GTKO), GTKO/β4GalNT2KO (that do not express the "fourth" xenoantigen), and TKO pig peripheral blood mononuclear cells (PBMCs) using 72 baboon sera (30 specific pathogen-free [SPF], and 42 non-SPF baboons). RESULTS Mean IgM antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to GTKO or TKO pig PBMCs (P < 0.01). Mean IgG antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to TKO PBMCs (P < 0.01). Mean CDC of GTKO/β4GalNT2KO pig PBMCs was significantly lower than of GTKO or TKO pig PBMCs (P < 0.01). SPF baboon serum IgM and IgG binding to, and CDC of, GTKO/β4GalNT2KO or TKO PBMCs were significantly lower than non-SPF baboon sera (P < 0.01). CONCLUSIONS Although TKO pigs form the basis for proposed clinical trials of xenotransplantation, it is difficult to identify baboons with a low or negative CDC to TKO pigs. For pig-to-baboon organ transplantation, the use of GTKO/β4GalNT2KO pigs would be preferable. The use of SPF baboons as recipients might be a minor advantage.
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Affiliation(s)
- Yehua Cui
- Department of Urology, Second Affiliated Hospital, University of South China, Hengyang City, Hunan, China
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Syed Sikandar Raza
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Mahmoud Morsi
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Huy Quoc Nguyen
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | | | - David K.C. Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
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29
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Xu S, Qin D, Yang H, He C, Liu W, Tian N, Wei Y, He X, Hua J, Peng S. SerpinB1 promotes the proliferation of porcine pancreatic stem cells through the STAT3 signaling pathway. J Steroid Biochem Mol Biol 2020; 198:105537. [PMID: 31785377 DOI: 10.1016/j.jsbmb.2019.105537] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 10/25/2019] [Accepted: 11/11/2019] [Indexed: 01/25/2023]
Abstract
Porcine pancreatic stem cells (pPSCs) can be induced to insulin-secreting cells and therefore considered the most promising seeding cells for curing human diabetes in future. However, insufficient pPSCs number is one of the bottleneck problems before its clinical application. SerpinB1 is a serine protease inhibitor in neutrophils and can directly promote the proliferation of β cells. Whether SerpinB1 is involved in pPSC proliferation and differentiation remains unknown. The effects of SerpinB1 on pPSCs proliferation were measured by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, qRT-PCR, western blot, and flow cytometry assays. We found that pPSCs did not efficiently reach the S phase when SerpinB1 expression was knocked down with short hairpin RNA (sh-SerpinB1), the expression of Cyclin D1, CDK-2, and PCNA also decreased. Meanwhile, cell viability and proliferation ability were both declined. Further analyses showed that the expression level of phosphorylated STAT3/STAT3was downregulated, along with an upregulation of p53 and p21. We used a two-step induction method to induce pPSCs to insulin-secreting cells and found that SerpinB1 expression in insulin-secreting cells was higher than in pPSCs. Meanwhile, the protein expression level of phosphorylated STAT3/STAT3 was increased while p53 and p21 was decreased in induced insulin-secreting cells in comparison with control cells. The insulin-secreting cells derived from the sh-SerpinB1 cells secreted less insulin and showed poor sensitivity to high glucose than control group. However, the insulin-secreting cells derived from the ov-SerpinB1 cells has a quite contrary tendency. In conclusion, this study demonstrates that SerpinB1 promotes the proliferation of pPSCs through the STAT3 signaling pathway, and SerpinB1 is a key factor for maintaining the viability of pPSCs during the transition to insulin-secreting cells.
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Affiliation(s)
- Shuanshuan Xu
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Dezhe Qin
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Hong Yang
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Chen He
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Wenqing Liu
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Na Tian
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Yudong Wei
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Xin He
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Jinlian Hua
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Sha Peng
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
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Abstract
There is a well-known worldwide shortage of deceased human donor organs for clinical transplantation. The transplantation of organs from genetically engineered pigs may prove an alternative solution. In the past 5 years, there have been sequential advances that have significantly increased pig graft survival in nonhuman primates. This progress has been associated with (1) the availability of increasingly sophisticated genetically engineered pigs; (2) the introduction of novel immunosuppressive agents, particularly those that block the second T-cell signal (costimulation blockade); (3) a better understanding of the inflammatory response to pig xenografts; and (4) increasing experience in the management of nonhuman primates with pig organ or cell grafts. The range of investigations required in experimental studies has increased. The standard immunologic assays are still carried out, but increasingly investigations aimed toward other pathobiologic barriers (e.g., coagulation dysregulation and inflammation) have become more important in determining injury to the graft.Now that prolonged graft survival, extending to months or even years, is increasingly being obtained, the function of the grafts can be more reliably assessed. If the source pigs are bred and housed under biosecure isolation conditions, and weaned early from the sow, most microorganisms can be eradicated from the herd. The potential risk of porcine endogenous retrovirus (PERV) infection remains unknown, but is probably small. Attention is being directed toward the selection of patients for the first clinical trials of xenotransplantation.
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Affiliation(s)
- David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
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Jorqui-Azofra M. Regulation of Clinical Xenotransplantation: A Reappraisal of the Legal, Ethical, and Social Aspects Involved. Xenotransplantation 2020; 2110:315-358. [DOI: 10.1007/978-1-0716-0255-3_20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Rodriguez S, Lau H, Corrales N, Heng J, Lee S, Stiner R, Alexander M, Lakey JRT. Characterization of chelator-mediated recovery of pancreatic islets from barium-stabilized alginate microcapsules. Xenotransplantation 2019; 27:e12554. [PMID: 31495985 DOI: 10.1111/xen.12554] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 07/29/2019] [Accepted: 08/07/2019] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Islet recovery from within alginate-based microcapsules is necessary for certain analytical assays like flow cytometry; however, this technology has not been widely characterized. In this study, we explore the ability of EDTA, EGTA, and sodium citrate to induce reverse alginate polymerization via chelation and assess the toxicity of each chelator on pancreatic islets. METHODS EDTA, EGTA, and sodium citrate were used to dissolve single-layered Ba2+ alginate encapsulated islets and the rate of capsule breakdown calculated from analysis of imaging data. The effect of chelator exposure on islet viability and recovery was assessed using flow cytometry, while glucose-stimulated insulin release (GSIR) assay was used to measure effects on islet function. RESULTS EGTA demonstrated the most rapid microcapsule dissolving rate followed by EDTA and sodium citrate. Islet recovery was significantly better when encapsulated islets were treated with EDTA than EGTA and Na+ citrate. A decrease in viability and increase in apoptotic cells were observed when encapsulated islets were treated with Na+ citrate compared to islets treated with EDTA and EGTA. Islets treated with EDTA and EGTA demonstrated comparable stimulation index values to non-treated control. Conversely, islets treated with Na+ citrate exhibited significantly decreased SI values compared to control. All chelator groups showed significantly lower insulin secretion than non-treated islets. CONCLUSION Islet recovery from alginate microcapsule is possible using common chelators like Na+ citrate, EDTA, and EGTA. Chelation of encapsulated islets using EDTA demonstrated the most efficient dissolving capabilities with the least toxicity toward islet recovery and health.
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Affiliation(s)
- Samuel Rodriguez
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Hien Lau
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Nicole Corrales
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Jennifer Heng
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Sarah Lee
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Rachel Stiner
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Jonathan R T Lakey
- Department of Surgery, University of California Irvine, Orange, CA, USA.,Department of Biomedical Engineering, University of California Irvine, Orange, CA, USA
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Hu S, de Vos P. Polymeric Approaches to Reduce Tissue Responses Against Devices Applied for Islet-Cell Encapsulation. Front Bioeng Biotechnol 2019; 7:134. [PMID: 31214587 PMCID: PMC6558039 DOI: 10.3389/fbioe.2019.00134] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022] Open
Abstract
Immunoisolation of pancreatic islets is a technology in which islets are encapsulated in semipermeable but immunoprotective polymeric membranes. The technology allows for successful transplantation of insulin-producing cells in the absence of immunosuppression. Different approaches of immunoisolation are currently under development. These approaches involve intravascular devices that are connected to the bloodstream and extravascular devices that can be distinguished in micro- and macrocapsules and are usually implanted in the peritoneal cavity or under the skin. The technology has been subject of intense fundamental research in the past decade. It has co-evolved with novel replenishable cell sources for cure of diseases such as Type 1 Diabetes Mellitus that need to be protected for the host immune system. Although the devices have shown significant success in animal models and even in human safety studies most technologies still suffer from undesired tissue responses in the host. Here we review the past and current approaches to modulate and reduce tissue responses against extravascular cell-containing micro- and macrocapsules with a focus on rational choices for polymer (combinations). Choices for polymers but also choices for crosslinking agents that induce more stable and biocompatible capsules are discussed. Combining beneficial properties of molecules in diblock polymers or application of these molecules or other anti-biofouling molecules have been reviewed. Emerging are also the principles of polymer brushes that prevent protein and cell-adhesion. Recently also immunomodulating biomaterials that bind to specific immune receptors have entered the field. Several natural and synthetic polymers and even combinations of these polymers have demonstrated significant improvement in outcomes of encapsulated grafts. Adequate polymeric surface properties have been shown to be essential but how the surface should be composed to avoid host responses remains to be identified. Current insight is that optimal biocompatible devices can be created which raises optimism that immunoisolating devices can be created that allows for long term survival of encapsulated replenishable insulin-producing cell sources for treatment of Type 1 Diabetes Mellitus.
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Affiliation(s)
- Shuixan Hu
- Division of Medical Biology, Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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Vanderschelden R, Sathialingam M, Alexander M, Lakey JRT. Cost and Scalability Analysis of Porcine Islet Isolation for Islet Transplantation: Comparison of Juvenile, Neonatal and Adult Pigs. Cell Transplant 2019; 28:967-972. [PMID: 31037984 PMCID: PMC6719497 DOI: 10.1177/0963689719847460] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The limited availability of human islets has led to the examination of porcine islets as a source of clinically suitable tissue for transplantation in patients with diabetes mellitus. Islets from porcine donors are commonly used in both in vitro and in vivo experiments studying diabetes mellitus. However, there are significant differences in quality and quantity of islet yield depending on donor pig age, as well as substantial differences in the costs of pancreas procurement in adult versus neonatal and juvenile pigs. In this study, we compared the total cost per islet of juvenile pig pancreata with that of neonatal and adult pigs. Although adult porcine pancreata yield, on average, more than five times the amount of islets than do juvenile and neonatal pancreata, we found that the high price of adult pigs led to the cost per islet being more than twice that of juvenile and neonatal islets (US $0.09 vs $0.04 and $0.02, respectively). In addition, neonatal and juvenile islets are advantageous in their scalability and retention of viability after culture. Our findings indicate that isolating neonatal and juvenile porcine islets is more cost-effective and scalable than isolating adult porcine islets.
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Affiliation(s)
- Rachel Vanderschelden
- 1 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, USA.,2 Department of Surgery, University of California, Irvine, USA
| | | | - Michael Alexander
- 1 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, USA.,2 Department of Surgery, University of California, Irvine, USA.,3 Department of Biomedical Engineering, University of California, Irvine, USA
| | - Jonathan R T Lakey
- 1 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, USA.,2 Department of Surgery, University of California, Irvine, USA.,3 Department of Biomedical Engineering, University of California, Irvine, USA
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35
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36
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Noordergraaf J, Schucker A, Martin M, Schuurman HJ, Ordway B, Cooley K, Sheffler M, Theis K, Armstrong C, Klein L, Hansen D, Olson M, Schlechter L, Spizzo T. Pathogen elimination and prevention within a regulated, Designated Pathogen Free, closed pig herd for long-term breeding and production of xenotransplantation materials. Xenotransplantation 2019; 25:e12428. [PMID: 30264879 PMCID: PMC7169735 DOI: 10.1111/xen.12428] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 05/21/2018] [Accepted: 05/25/2018] [Indexed: 12/23/2022]
Abstract
BACKGROUND We established a Source Animal (barrier) Facility (SAF) for generating designated pathogen-free (DPF) pigs to serve as donors of viable organs, tissues, or cells for xenotransplantation into clinical patients. This facility was populated with caesarian derived, colostrum deprived (CDCD) piglets, from sows of conventional-specific (or specified) pathogen-free (SPF) health status in six cohorts over a 10-month period. In all cases, CDCD piglets fulfilled DPF status including negativity for porcine circovirus (PCV), a particularly environmentally robust and difficult to inactivate virus which at the time of SAF population was epidemic in the US commercial swine production industry. Two outbreaks of PCV infection were subsequently detected during sentinel testing. The first occurred several weeks after PCV-negative animals were moved under quarantine from the nursery into an animal holding room. The apparent origin of PCV was newly installed stainless steel penning, which was not sufficiently degreased thereby protecting viral particles from disinfection. The second outbreak was apparently transmitted via employee activities in the Caesarian-section suite adjacent to the barrier facility. In both cases, PCV was contained in the animal holding room where it was diagnosed making a complete facility depopulation-repopulation unnecessary. METHOD Infectious PCV was eliminated during both outbreaks by the following: euthanizing infected animals, disposing of all removable items from the affected animal holding room, extensive cleaning with detergents and degreasing agents, sterilization of equipment and rooms with chlorine dioxide, vaporized hydrogen peroxide, and potassium peroxymonosulfate, and for the second outbreak also glutaraldehyde/quaternary ammonium. Impact on other barrier animals throughout the process was monitored by frequent PCV diagnostic testing. RESULT After close monitoring for 6 months indicating PCV absence from all rooms and animals, herd animals were removed from quarantine status. CONCLUSION Ten years after PCV clearance following the second outbreak, due to strict adherence to biosecurity protocols and based on ongoing sentinel diagnostic monitoring (currently monthly), the herd remains DPF including PCV negative.
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Affiliation(s)
| | | | | | | | | | | | | | - Kara Theis
- Spring Point Project, Minneapolis, MN, USA
| | | | | | | | | | | | - Tom Spizzo
- Spring Point Project, Minneapolis, MN, USA
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37
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Jiang XF, Qian TL, Chen D, Lu HW, Xue P, Yang XW, Zhang LH, Hu YZ, Zhang DW. Correction of Hyperglycemia in Diabetic Rats With the Use of Microencapsulated Young Market Pig Islets. Transplant Proc 2018; 50:3895-3899. [PMID: 30577283 DOI: 10.1016/j.transproceed.2018.09.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 08/24/2018] [Accepted: 09/05/2018] [Indexed: 11/24/2022]
Abstract
OBJECTIVE The aim of this work was to investigate the transplantation efficacy of microencapsulated young market pig islets in a diabetic rat model. METHODS Islets were isolated and purified from young market pigs obtained from a local slaughterhouse. The islets were encapsulated in barium alginate and subjected to a glucose-induced insulin release functional assay in culture. Microencapsulated islets were transplanted into diabetic Sprague-Dawley rats and removed after 30 days for histologic examination. RESULTS The mean islet equivalent (IEQ) yield per gram of digested tissue was 3,125 ± 617 IEQ/g after isolation and 2,618 ± 917 IEQ/g after purification, respectively. Host rats' blood glucose concentrations normalized (from 22.3 ± 2.7 mmol/L to 5.1 ± 0.67 mmol/L) following encapsulated islet transplantation. After graft removal, hyperglycemia recurred in the rats, indicating that the grafts were responsible for maintaining euglycemia. Histology revealed viable islets in the capsules 30 days after graft removal. Immunolabeling of insulin verified that β-cells within the capsules remained well granulated. No fibrosis or immune cells were found in histopathology. CONCLUSIONS Barium alginate encapsulation of young market pig islets can normalize glucose regulation in diabetic rats without fibrosis or an immunologic response.
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Affiliation(s)
- X-F Jiang
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - T-L Qian
- Department of Anesthesiology, Shenzhen Shekou People's Hospital, Shenzhen, People's Republic of China
| | - D Chen
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - H-W Lu
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - P Xue
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - X-W Yang
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - L-H Zhang
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Y-Z Hu
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - D-W Zhang
- Department of Surgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
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Abstract
Biologics now constitute a significant element of available medical treatments. Owing to their clinical and commercial success, biologics are a rapidly growing class and have become a dominant therapeutic modality. Although most of the successful biologics to date are drugs that bear a peptidic backbone, ranging from small peptides to monoclonal antibodies (~500 residues; 150 kDa), new biologic modalities, such as nucleotide-based therapeutics and viral gene therapies, are rapidly maturing towards widespread clinical use. Given the rise of peptides and proteins in the pharmaceutical landscape, tremendous research and development interest exists in developing less-invasive or non-invasive routes for the systemic delivery of biologics, including subcutaneous, transdermal, oral, inhalation, nasal and buccal routes. This Review summarizes the current status, latest updates and future prospects for such delivery of peptides, proteins and other biologics.
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39
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Sykes M. IXA Honorary Member Lecture, 2017: The long and winding road to tolerance. Xenotransplantation 2018; 25:e12419. [PMID: 29913040 DOI: 10.1111/xen.12419] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/03/2018] [Indexed: 12/18/2022]
Abstract
The last 15 years or so have seen exciting progress in xenotransplantation, with porcine organ grafts surviving months or even years in non-human primates. These advances reflect the application of new scientific knowledge, improved immunosuppressive agents, and genetic engineering. The field has recently enjoyed a renaissance of interest and hope, largely due to the exponential increase in our capacity to genetically engineer porcine source animals. However, immune responses to xenografts are very powerful and widespread clinical application of xenotransplantation will depend on the ability to suppress these immune responses while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. Our work over the last three decades has aimed to engineer the immune system of the recipient in a manner that achieves specific tolerance to the xenogeneic donor while preserving otherwise normal immune function. Important proofs of principle have been obtained, first in rodents, and later in human immune systems in "humanized mice" and finally in non-human primates, demonstrating the capacity and potential synergy of mixed xenogeneic chimerism and xenogeneic thymic transplantation in tolerizing multiple arms of the immune system. Considering the fact that clinical tolerance has recently been achieved for allografts and the even greater importance of avoiding excessive immunosuppression for xenografts, it is my belief that it is both possible and imperative that we likewise achieve xenograft tolerance. I expect this to be accomplished through the availability of targeted approaches to recipient immune conditioning, understanding of immunological mechanisms of tolerance, advanced knowledge of physiological incompatibilities, and the availability of inbred miniature swine with optimized use of genetic engineering.
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Affiliation(s)
- Megan Sykes
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.,Department of Medicine, Columbia University, New York, NY, USA.,Department of Microbiology & Immunology, Columbia University, New York, NY, USA.,Department of Surgery, Columbia University, New York, NY, USA
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40
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Ekser B, Cooper DKC. Xenotransplantation research and the 'International Journal of Surgery'. Int J Surg 2018; 58:57-59. [PMID: 30237083 DOI: 10.1016/j.ijsu.2018.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 11/23/2022]
Affiliation(s)
- Burcin Ekser
- Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
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Safley SA, Kenyon NS, Berman DM, Barber GF, Willman M, Duncanson S, Iwakoshi N, Holdcraft R, Gazda L, Thompson P, Badell IR, Sambanis A, Ricordi C, Weber CJ. Microencapsulated adult porcine islets transplanted intraperitoneally in streptozotocin-diabetic non-human primates. Xenotransplantation 2018; 25:e12450. [PMID: 30117193 DOI: 10.1111/xen.12450] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 05/18/2018] [Accepted: 06/26/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Xenogeneic donors would provide an unlimited source of islets for the treatment of type 1 diabetes (T1D). The goal of this study was to assess the function of microencapsulated adult porcine islets (APIs) transplanted ip in streptozotocin (STZ)-diabetic non-human primates (NHPs) given targeted immunosuppression. METHODS APIs were encapsulated in: (a) single barium-gelled alginate capsules or (b) double alginate capsules with an inner, islet-containing compartment and a durable, biocompatible outer alginate layer. Immunosuppressed, streptozotocin-diabetic NHPs were transplanted ip with encapsulated APIs, and graft function was monitored by measuring blood glucose, %HbA1c, and porcine C-peptide. At graft failure, explanted capsules were assessed for biocompatibility and durability plus islet viability and functionality. Host immune responses were evaluated by phenotyping peritoneal cell populations, quantitation of peritoneal cytokines and chemokines, and measurement of anti-porcine IgG and IgM plus anti-Gal IgG. RESULTS NHP recipients had reduced hyperglycemia, decreased exogenous insulin requirements, and lower percent hemoglobin A1c (%HbA1c) levels. Porcine C-peptide was detected in plasma of all recipients, but these levels diminished with time. However, relatively high levels of porcine C-peptide were detected locally in the peritoneal graft site of some recipients at sacrifice. IV glucose tolerance tests demonstrated metabolic function, but the grafts eventually failed in all diabetic NHPs regardless of the type of encapsulation or the host immunosuppression regimen. Explanted microcapsules were intact, "clean," and free-floating without evidence of fibrosis at graft failure, and some reversed diabetes when re-implanted ip in diabetic immunoincompetent mice. Histology of explanted capsules showed scant evidence of a host cellular response, and viable islets could be found. Flow cytometric analyses of peritoneal cells and peripheral blood showed similarly minimal evidence of a host immune response. Preformed anti-porcine IgG and IgM antibodies were present in recipient plasma, but these levels did not rise post-transplant. Peritoneal graft site cytokine or chemokine levels were equivalent to normal controls, with the exception of minimal elevation observed for IL-6 or IL-1β, GRO-α, I-309, IP-10, and MCP-1. However, we found central necrosis in many of the encapsulated islets after graft failure, and explanted islets expressed endogenous markers of hypoxia (HIF-1α, osteopontin, and GLUT-1), suggesting a role for non-immunologic factors, likely hypoxia, in graft failure. CONCLUSIONS With donor xenoislet microencapsulation and host immunosuppression, APIs corrected hyperglycemia after ip transplantation in STZ-diabetic NHPs in the short term. The islet xenografts lost efficacy gradually, but at graft failure, some viable islets remained, substantial porcine C-peptide was detected in the peritoneal graft site, and there was very little evidence of a host immune response. We postulate that chronic effects of non-immunologic factors, such as in vivo hypoxic and hyperglycemic conditions, damaged the encapsulated islet xenografts. To achieve long-term function, new approaches must be developed to prevent this damage, for example, by increasing the oxygen supply to microencapsulated islets in the ip space.
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Affiliation(s)
- Susan A Safley
- Department of Surgery, Emory University, Atlanta, Georgia
| | - Norma S Kenyon
- Diabetes Research Institute, Miami, Florida.,Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Microbiology & Immunology, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Dora M Berman
- Diabetes Research Institute, Miami, Florida.,Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Microbiology & Immunology, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida
| | | | | | - Stephanie Duncanson
- Department of Biomedical Engineering, School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia
| | - Neal Iwakoshi
- Department of Surgery, Emory University, Atlanta, Georgia
| | | | | | - Peter Thompson
- Department of Surgery, Emory University, Atlanta, Georgia
| | - I Raul Badell
- Department of Surgery, Emory University, Atlanta, Georgia
| | - Athanassios Sambanis
- Department of Biomedical Engineering, School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia
| | - Camillo Ricordi
- Diabetes Research Institute, Miami, Florida.,Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Microbiology & Immunology, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida.,Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
| | - Collin J Weber
- Department of Surgery, Emory University, Atlanta, Georgia
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42
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Pellegrini S, Piemonti L, Sordi V. Pluripotent stem cell replacement approaches to treat type 1 diabetes. Curr Opin Pharmacol 2018; 43:20-26. [PMID: 30071348 DOI: 10.1016/j.coph.2018.07.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/06/2018] [Accepted: 07/16/2018] [Indexed: 12/13/2022]
Abstract
Stem cells represent a potential candidate for β cell replacement in type 1 diabetes. Pluripotent stem cells are able to differentiate in vitro into functional insulin producing cells, that can restore normoglycemia in diabetic mice. Clinical trials with embryonic stem cell-derived pancreatic progenitors are ongoing. Besides, induced pluripotent stem cells offer the chance of personalized cell therapy. So far, transition to the clinic still needs to face critical issues, such as immunogenicity and safety of stem cell derived β cells. To this purpose, new strategies for immunoprotection, including micro and macro-encapsulation, but also gene editing approaches, are being explored.
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Affiliation(s)
- Silvia Pellegrini
- Diabetes Research Institute - IRCCS San Raffaele Scientific Institute, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute - IRCCS San Raffaele Scientific Institute, Italy; Vita-Salute San Raffaele University, Italy
| | - Valeria Sordi
- Diabetes Research Institute - IRCCS San Raffaele Scientific Institute, Italy.
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43
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Bottino R, Knoll MF, Knoll CA, Bertera S, Trucco MM. The Future of Islet Transplantation Is Now. Front Med (Lausanne) 2018; 5:202. [PMID: 30057900 PMCID: PMC6053495 DOI: 10.3389/fmed.2018.00202] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022] Open
Abstract
Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.
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Affiliation(s)
- Rita Bottino
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
- College of Medicine, Drexel University, Philadelphia, PA, United States
| | - Michael F. Knoll
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Carmela A. Knoll
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Suzanne Bertera
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Massimo M. Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
- College of Medicine, Drexel University, Philadelphia, PA, United States
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44
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Wang R, Ruan M, Zhang R, Chen L, Li X, Fang B, Li C, Ren X, Liu J, Xiong Q, Zhang L, Jin Y, Li L, Li R, Wang Y, Yang H, Dai Y. Antigenicity of tissues and organs from GGTA1/CMAH/β4GalNT2 triple gene knockout pigs. J Biomed Res 2018; 33:235. [PMID: 30007952 PMCID: PMC6813527 DOI: 10.7555/jbr.32.20180018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/23/2018] [Indexed: 12/17/2022] Open
Abstract
Clinical xenotransplantations have been hampered by human preformed antibody-mediated damage of the xenografts. To overcome biological incompatibility between pigs and humans, one strategy is to remove the major antigens [Gal, Neu5Gc, and Sd(a)] present on pig cells and tissues. Triple gene (GGTA1, CMAH, and β 4GalNT2) knockout (TKO) pigs were produced in our laboratory by CRISPR-Cas9 targeting. To investigate the antigenicity reduction in the TKO pigs, the expression levels of these three xenoantigens in the cornea, heart, liver, spleen, lung, kidney, and pancreas tissues were examined. The level of human IgG/IgM binding to those tissues was also investigated, with wildtype pig tissues as control. The results showed that αGal, Neu5Gc, and Sd(a) were markedly positive in all the examined tissues in wildtype pigs but barely detected in TKO pigs. Compared to wildtype pigs, the liver, spleen, and pancreas of TKO pigs showed comparable levels of human IgG and IgM binding, whereas corneas, heart, lung, and kidney of TKO pigs exhibited significantly reduced human IgG and IgM binding. These results indicate that the antigenicity of TKO pig is significantly reduced and the remaining xenoantigens on porcine tissues can be eliminated via a gene targeting approach.
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Affiliation(s)
| | | | | | - Lei Chen
- Jiangsu Key Laboratory of Xenotransplantation
| | - Xiaoxue Li
- Jiangsu Key Laboratory of Xenotransplantation
| | - Bin Fang
- Jiangsu Key Laboratory of Xenotransplantation
| | - Chu Li
- Jiangsu Key Laboratory of Xenotransplantation
| | - Xueyang Ren
- Jiangsu Key Laboratory of Xenotransplantation
| | - Jiying Liu
- Jiangsu Key Laboratory of Xenotransplantation
| | - Qiang Xiong
- Jiangsu Key Laboratory of Xenotransplantation
| | | | - Yong Jin
- Jiangsu Key Laboratory of Xenotransplantation
| | - Lin Li
- Jiangsu Key Laboratory of Xenotransplantation
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
| | - Rongfeng Li
- Jiangsu Key Laboratory of Xenotransplantation
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
| | - Ying Wang
- Jiangsu Key Laboratory of Xenotransplantation
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
| | - Haiyuan Yang
- Jiangsu Key Laboratory of Xenotransplantation
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- 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 518035, China
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45
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Yang KC, Yanai G, Yang SY, Canning P, Satou Y, Kawagoe M, Sumi S. Low-adhesive ethylene vinyl alcohol-based packaging to xenogeneic islet encapsulation for type 1 diabetes treatment. Biotechnol Bioeng 2018; 115:2341-2355. [PMID: 29777589 DOI: 10.1002/bit.26730] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 03/17/2018] [Accepted: 05/16/2018] [Indexed: 01/16/2023]
Abstract
Transplantation of encapsulated porcine islets is proposed to treat type 1 diabetes. However, the envelopment of fibrous tissue and the infiltration of immune cells impair islet function and eventually cause implant failure. It is known that hemodialysis using an ethylene vinyl alcohol (EVOH) membrane results in minor tissue responses. Therefore, we hypothesized that using a low-adhesive EVOH membrane for encapsulation may prevent host cell accumulation and fibrous capsule formation. In this study, rat islets suspended in chitosan gel were encapsulated in bags made from highly porous EVOH membranes, and their in vitro insulin secretion function as well as in vivo performance was evaluated. The results showed that the EVOH bag did not affect islet survival or glucose-stimulated insulin secretion. Whereas naked islets were dysfunctional after 7 days of culture in vitro, islets within the EVOH bag produced insulin continuously for 30 days. Streptozotocin-induced diabetic mice were given islets-chitosan gel-EVOH implants intraperitoneally (650-800 islets equivalent) and exhibited lower blood glucose levels and regained body weight during a 4-week observation period. The transplanted mice had higher levels of serum insulin and C-peptide, with an improved blood glucose disappearance rate. Retrieved implants had minor tissue adhesion, and histology showed a limited number of mononuclear cells and fibroblasts surrounding the implants. No invasion of host cells into the EVOH bags was noticed, and the encapsulated islets were intact and positive for insulin-glucagon immunostaining. In conclusion, an EVOH bag can protect encapsulated islets, limit fibrous capsule formation, and extend graft function.
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Affiliation(s)
- Kai-Chiang Yang
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Goichi Yanai
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Sin-Yu Yang
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Priyadarshini Canning
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yoshio Satou
- Molding Component Business Department, Kuraray Co., Ltd, Tokyo, Japan
| | - Masako Kawagoe
- Molding Component Business Department, Kuraray Co., Ltd, Tokyo, Japan
| | - Shoichiro Sumi
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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46
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Crossan C, Mourad NI, Smith K, Gianello P, Scobie L. Assessment of porcine endogenous retrovirus transmission across an alginate barrier used for the encapsulation of porcine islets. Xenotransplantation 2018; 25:e12409. [DOI: 10.1111/xen.12409] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 04/13/2018] [Accepted: 04/16/2018] [Indexed: 01/21/2023]
Affiliation(s)
- Claire Crossan
- Department of Biological and Biomedical Sciences; School of Health and Life Sciences; Glasgow Caledonian University; Glasgow UK
| | - Nizar I. Mourad
- Laboratoire de Chirurgie Expérimentale et Transplantation; Université Catholique de Louvain; Brussels Belgium
| | - Karen Smith
- Department of Biological and Biomedical Sciences; School of Health and Life Sciences; Glasgow Caledonian University; Glasgow UK
| | - Pierre Gianello
- Laboratoire de Chirurgie Expérimentale et Transplantation; Université Catholique de Louvain; Brussels Belgium
| | - Linda Scobie
- Department of Biological and Biomedical Sciences; School of Health and Life Sciences; Glasgow Caledonian University; Glasgow UK
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47
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Saleh LS, Bryant SJ. In Vitro and In Vivo Models for Assessing the Host Response to Biomaterials. ACTA ACUST UNITED AC 2018; 24:13-21. [PMID: 30479632 DOI: 10.1016/j.ddmod.2018.04.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The foreign body response (FBR) occurs ubiquitously to essentially all non-biological materials that are implanted into higher organisms. The FBR is characterized by inflammation followed by fibrosis and is mediated largely by macrophages. While many current medical devices tolerate the FBR, the FBR is responsible for many asceptic device failures and is hindering advancements of new devices that rely on device-host communication to function. To this end, in vitro and in vivo models are critical to studying how a biomaterial, via its chemistry and properties, affect the FBR. This short review highlights the main in vitro and in vivo models that are used to study the FBR. In vitro models that capture macrophage interrogation of a biomaterial and evaluation of macrophage attachment, polarization and fusion are described. In vivo models using rodents, which provide a relatively simple model of the complex FBR process, and human-relevant nonhuman primate models are described. Collectively, the combination of in vitro and in vivo models will help advance our fundmental understanding of the FBR and enable new biomaterials to be developed that can effectively modulate the FBR to achieve a desire device-host outcome.
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Affiliation(s)
- Leila S Saleh
- Department of Chemical and Biological Engineering, University of Colorado, 3415 Colorado Avenue, Boulder, CO 80303, USA
| | - Stephanie J Bryant
- Department of Chemical and Biological Engineering, University of Colorado, 3415 Colorado Avenue, Boulder, CO 80303, USA.,BioFrontiers Institute, University of Colorado, 3415 Colorado Avenue, Boulder, CO 80303, USA.,Material Science and Engineering Program, University of Colorado, 3415 Colorado Avenue, Boulder, CO 80303, USA
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Denner J, Scobie L, Schuurman HJ. Is it currently possible to evaluate the risk posed by PERVs for clinical xenotransplantation? Xenotransplantation 2018; 25:e12403. [DOI: 10.1111/xen.12403] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 04/13/2018] [Indexed: 12/23/2022]
Affiliation(s)
| | - Linda Scobie
- School of Health and Life Sciences; Glasgow Caledonian University; Glasgow UK
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49
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Denner J. Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology 2018; 15:28. [PMID: 29609635 PMCID: PMC5879552 DOI: 10.1186/s12977-018-0411-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 03/22/2018] [Indexed: 01/27/2023] Open
Abstract
Porcine endogenous retroviruses (PERVs) are present in the genome of all pigs, they infect certain human cells and therefore pose a special risk for xenotransplantation using pig cells, tissues and organs. Xenotransplantation is being developed in order to alleviate the reduced availability of human organs. Despite the fact that PERVs are able to infect certain human cells and cells from other species, transmission of PERVs has not been observed when animals (including non-human primates) were inoculated with PERV preparations or during preclinical xenotransplantations. The data indicate that PERVs were not transmitted because they were not released from the transplant or were inhibited by intracellular restriction factors and innate immunity in the recipient. In a single study in guinea pigs, a transient PERV infection and anti-PERV antibodies were described, indicating that in this case at least, the immune system may also have been involved.
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Affiliation(s)
- Joachim Denner
- Robert Koch Institute, Nordufer 20, 13353, Berlin, Germany.
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Abstract
PURPOSE OF REVIEW Porcine islets are being extensively investigated as alternative sources of insulin-secreting cells for transplantation in insulin-dependent diabetic patients. The present review focuses on recent advances in porcine islet transplantation with particular emphasis on new transgenic pig models, islet encapsulation, and biosafety considerations. RECENT FINDINGS Genetic modifications aimed to reduce islet cell immunogenicity, to prolong their survival, and to improve their secretory function have been reported. Micro- and macroencapsulation of porcine islets should allow their use in the clinic with no or minimal immunosuppression. The risk of porcine endogenous retrovirus transmission is being re-evaluated since no evidence for infection was found in several clinical and preclinical studies. SUMMARY Pig islet xenotransplantation is still a serious contestant in the race for novel treatments for type I diabetes. Adequate pathogen screening, animal selection, and the establishment of microbiological, genetic, and potency release quality controls should increase safety and efficacy of future porcine islets transplantation clinical trials.
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