Challenges and perspectives in xenoliver research: lessons from decedent and primate models

Liver xenotransplantation is a potential strategy to address the shortage of donor livers, either as a temporary bridge to allotransplantation, bridge to native liver recovery, or destination therapy. Advances in genetic engineering and immunosuppression have enabled liver xenografts to evade hyperacute rejection, yet durable graft survival remains elusive. Profound thrombocytopenia, consumptive coagulopathy, and xenotransplantation-associated thrombotic microangiopathy limit long-term graft survival. Evidence from nonhuman primates, decedents, and recent clinical models suggests that hematologic and physiologic species incompatibilities (in addition to classical immune-mediated rejection) constitute additional barriers to successful liver xenotransplantation. These problems are driven by species-specific platelet-endothelial interactions, dysregulated coagulation factor synthesis, and platelet sequestration within the xenograft. This review synthesizes lessons from decedent and primate xenoliver models, highlighting progress in this area to date, barriers to prolonged survival after liver xenotransplant, and directions for further research.