Current Barriers to Clinical Liver Xenotransplantation.
Current Barriers to Clinical Liver Xenotransplantation.
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DOI：
10.3389/fimmu.2022.827535
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发表时间：
2022
影响因子：
7.3
通讯作者：
Ekser B
中科院分区：
文献类型：
--
作者：
Cross-Najafi AA;Lopez K;Isidan A;Park Y;Zhang W;Li P;Yilmaz S;Akbulut S;Ekser B
猪到非人灵长类动物异种肝移植的临床前试验最近实现了更长的存活时间。然而，危及生命的血小板减少症和凝血功能失调继续将临床前异种肝移植物的存活时间限制在1个月以下，尽管猪进行了各种遗传修饰和强化的药理学支持。输注人凝血因子和复杂的免疫抑制方案已导致受体存活率的实质性改善。血小板减少症和凝血功能失调的基本生物学机制仍不完全清楚。目前的研究表明，猪血管性血友病因子与人血小板GPIb受体的结合更紧密，这是由于O-连接的糖基化增加，导致人血小板活化增加。猪肝窦内皮细胞和枯否细胞分别以脱唾液酸糖蛋白受体1依赖性和CD 40/CD 154依赖性方式吞噬人血小板。猪枯否细胞通过种属不相容的SIRPα/CD 47轴吞噬人血小板。凝血失调的关键驱动因素包括由于猪组织因子途径抑制剂未能抑制受体组织因子而导致的外源性凝血级联的组成性激活。此外，猪血栓调节蛋白在与人凝血酶结合时不能激活人蛋白C，导致高凝状态。这些关键基因的联合遗传修饰可能会减轻肝脏异种移植诱导的血小板减少症和凝血功能失调，从而提高猪到非人灵长类动物肝脏异种移植的受体存活率，并可能成为第一个猪到人的临床试验。
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.