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Current Barriers to Clinical Liver Xenotransplantation
Preclinical trials of pig-to-nonhuman primate liver xenotransplantation have recently achieved longer survival times. However, life-threatening thrombocytopenia and coagulation dysregulation continue to limit preclinical liver xenograft survival times to less than one month despite various genetic m...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904558/ https://www.ncbi.nlm.nih.gov/pubmed/35281047 http://dx.doi.org/10.3389/fimmu.2022.827535 |
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author | Cross-Najafi, Arthur A. Lopez, Kevin Isidan, Abdulkadir Park, Yujin Zhang, Wenjun Li, Ping Yilmaz, Sezai Akbulut, Sami Ekser, Burcin |
author_facet | Cross-Najafi, Arthur A. Lopez, Kevin Isidan, Abdulkadir Park, Yujin Zhang, Wenjun Li, Ping Yilmaz, Sezai Akbulut, Sami Ekser, Burcin |
author_sort | Cross-Najafi, Arthur A. |
collection | PubMed |
description | Preclinical trials of pig-to-nonhuman primate liver xenotransplantation have recently achieved longer survival times. However, life-threatening thrombocytopenia and coagulation dysregulation continue to limit preclinical liver xenograft survival times to less than one month despite various genetic modifications in pigs and intensive pharmacological support. Transfusion of human coagulation factors and complex immunosuppressive regimens have resulted in substantial improvements in recipient survival. The fundamental biological mechanisms of thrombocytopenia and coagulation dysregulation remain incompletely understood. Current studies demonstrate that porcine von Willebrand Factor binds more tightly to human platelet GPIb receptors due to increased O-linked glycosylation, resulting in increased human platelet activation. Porcine liver sinusoidal endothelial cells and Kupffer cells phagocytose human platelets in an asialoglycoprotein receptor 1-dependent and CD40/CD154-dependent manner, respectively. Porcine Kupffer cells phagocytose human platelets via a species-incompatible SIRPα/CD47 axis. Key drivers of coagulation dysregulation include constitutive activation of the extrinsic clotting cascade due to failure of porcine tissue factor pathway inhibitor to repress recipient tissue factor. Additionally, porcine thrombomodulin fails to activate human protein C when bound by human thrombin, leading to a hypercoagulable state. Combined genetic modification of these key genes may mitigate liver xenotransplantation-induced thrombocytopenia and coagulation dysregulation, leading to greater recipient survival in pig-to-nonhuman primate liver xenotransplantation and, potentially, the first pig-to-human clinical trial. |
format | Online Article Text |
id | pubmed-8904558 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89045582022-03-10 Current Barriers to Clinical Liver Xenotransplantation Cross-Najafi, Arthur A. Lopez, Kevin Isidan, Abdulkadir Park, Yujin Zhang, Wenjun Li, Ping Yilmaz, Sezai Akbulut, Sami Ekser, Burcin Front Immunol Immunology Preclinical trials of pig-to-nonhuman primate liver xenotransplantation have recently achieved longer survival times. However, life-threatening thrombocytopenia and coagulation dysregulation continue to limit preclinical liver xenograft survival times to less than one month despite various genetic modifications in pigs and intensive pharmacological support. Transfusion of human coagulation factors and complex immunosuppressive regimens have resulted in substantial improvements in recipient survival. The fundamental biological mechanisms of thrombocytopenia and coagulation dysregulation remain incompletely understood. Current studies demonstrate that porcine von Willebrand Factor binds more tightly to human platelet GPIb receptors due to increased O-linked glycosylation, resulting in increased human platelet activation. Porcine liver sinusoidal endothelial cells and Kupffer cells phagocytose human platelets in an asialoglycoprotein receptor 1-dependent and CD40/CD154-dependent manner, respectively. Porcine Kupffer cells phagocytose human platelets via a species-incompatible SIRPα/CD47 axis. Key drivers of coagulation dysregulation include constitutive activation of the extrinsic clotting cascade due to failure of porcine tissue factor pathway inhibitor to repress recipient tissue factor. Additionally, porcine thrombomodulin fails to activate human protein C when bound by human thrombin, leading to a hypercoagulable state. Combined genetic modification of these key genes may mitigate liver xenotransplantation-induced thrombocytopenia and coagulation dysregulation, leading to greater recipient survival in pig-to-nonhuman primate liver xenotransplantation and, potentially, the first pig-to-human clinical trial. Frontiers Media S.A. 2022-02-23 /pmc/articles/PMC8904558/ /pubmed/35281047 http://dx.doi.org/10.3389/fimmu.2022.827535 Text en Copyright © 2022 Cross-Najafi, Lopez, Isidan, Park, Zhang, Li, Yilmaz, Akbulut and Ekser https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Cross-Najafi, Arthur A. Lopez, Kevin Isidan, Abdulkadir Park, Yujin Zhang, Wenjun Li, Ping Yilmaz, Sezai Akbulut, Sami Ekser, Burcin Current Barriers to Clinical Liver Xenotransplantation |
title | Current Barriers to Clinical Liver Xenotransplantation |
title_full | Current Barriers to Clinical Liver Xenotransplantation |
title_fullStr | Current Barriers to Clinical Liver Xenotransplantation |
title_full_unstemmed | Current Barriers to Clinical Liver Xenotransplantation |
title_short | Current Barriers to Clinical Liver Xenotransplantation |
title_sort | current barriers to clinical liver xenotransplantation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904558/ https://www.ncbi.nlm.nih.gov/pubmed/35281047 http://dx.doi.org/10.3389/fimmu.2022.827535 |
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