Current Barriers to Clinical Liver Xenotransplantation

Abstract

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.

Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers

“…[3] Xenotransplantation of organs from genetically engineered swine has seen a wave of recent progress in kidney and heart transplantation [4,5] but lags behind in liver transplantation. [6] Currently, the most clinically used method for enhanced preservation of high-risk donor livers is by machine perfusion. Compared with static cold storage, machine perfusion allows continuous delivery of oxygen and nutrients, permits an opportunity to evaluate graft viability ex vivo, and is associated with decreased rates of biliary complications and early allograft dysfunction.…”

“…Split-liver transplantation is associated with increased technical complexity and post-transplant complications 3 . Xenotransplantation of organs from genetically engineered swine has seen a wave of recent progress in kidney and heart transplantation 4,5 but lags behind in liver transplantation 6 …”

Auxiliary liver xenotransplantation technique in a transgenic pig‐to‐non‐human primate model: A surgical approach to prolong survival

“…Recent advancements in genetic engineering and immunosuppressive therapies have rekindled interest in xenotransplantation, particularly using genetically modified pigs as potential organ donors. Ongoing research aims to enhance the safety and effectiveness of xenotransplants 6 …”

Opinions of nursing and theology faculty students on Xenotransplantation

“…Every year, thousands of people around the world face end‐stage organ failure and its complications, and unfortunately the ultimate cure for this trouble condition is organ transplantation (Tx) 1 . However, the growing gap between the number of people who need organ Tx and the donor pool continues to be the most important agenda item in the Tx community.…”

“…Therefore, most of individuals waiting for a Tx continue to wait for another year, and inevitably, some of them lose their lives while on the waiting list 2–5 . This problem leads to pigs being an acceptable option for an alternative organ source, thus causing xenotransplantation (XTx), so called transplanting organs from one species to another, to be preferred as an advantageous, unlimited “donor” organ source 1,2 . Accordingly, studies on XTx have progressed in recent years, and pigs can be accepted as an alternative organ source for humans ethically 3,5 .…”