Current Barriers to Clinical Liver Xenotransplantation

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dc.authoridEkser, Burcin/0000-0003-0741-8007
dc.authoridAkbulut, Sami/0000-0002-6864-7711
dc.authoridYilmaz, Sezai/0000-0002-8044-0297
dc.authoridCross-Najafi, Arthur/0000-0003-1536-0300
dc.authoridLopez, Kevin/0000-0002-5807-3136
dc.authorwosidEkser, Burcin/I-3288-2019
dc.authorwosidAkbulut, Sami/L-9568-2014
dc.authorwosidYilmaz, Sezai/ABI-2323-2020
dc.contributor.authorCross-Najafi, Arthur A.
dc.contributor.authorLopez, Kevin
dc.contributor.authorIsidan, Abdulkadir
dc.contributor.authorPark, Yujin
dc.contributor.authorZhang, Wenjun
dc.contributor.authorLi, Ping
dc.contributor.authorYilmaz, Sezai
dc.date.accessioned2024-08-04T20:51:45Z
dc.date.available2024-08-04T20:51:45Z
dc.date.issued2022
dc.departmentİnönü Üniversitesien_US
dc.description.abstractPreclinical 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 SIRP alpha/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.en_US
dc.description.sponsorshipDepartment of Surgery [VFR-457-Ekser]; Indiana Clinical and Translational Sciences Institute [UL1TR001108]; National Institutes of Health (NIH); National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award; NIH NIAID [R21AI164002]; National Institute of Allergy and Infectious Diseases [R21AI164002] Funding Source: NIH RePORTERen_US
dc.description.sponsorship& nbsp;Work on xenotransplantation at Indiana University has been supported by internal funds of the Department of Surgery, in part, with support by the Board of Directors of the Indiana University Health Values Fund for Research Award (VFR-457-Ekser), the Indiana Clinical and Translational Sciences Institute, funded in part by Grant # UL1TR001108 from the National Institutes of Health (NIH), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, and NIH NIAID R21AI164002.en_US
dc.identifier.doi10.3389/fimmu.2022.827535
dc.identifier.issn1664-3224
dc.identifier.pmid35281047en_US
dc.identifier.scopus2-s2.0-85126187868en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3389/fimmu.2022.827535
dc.identifier.urihttps://hdl.handle.net/11616/100533
dc.identifier.volume13en_US
dc.identifier.wosWOS:000767660000001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherFrontiers Media Saen_US
dc.relation.ispartofFrontiers in Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectliver xenotransplantationen_US
dc.subjectthrombocytopeniaen_US
dc.subjectxenograften_US
dc.subjectimmune rejectionen_US
dc.subjectporcineen_US
dc.titleCurrent Barriers to Clinical Liver Xenotransplantationen_US
dc.typeReview Articleen_US

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