Platelets stimulate liver regeneration in a rat model of partial liver transplantation
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1002/lt.25962
Abstract
Living donor liver transplantation (LDLT) is sometimes associated with impaired regeneration and severe ischemia/reperfusion (I/R) injury in the graft, resulting in small‐for‐size syndrome (SFSS). Platelets were previously reported to stimulate liver regeneration in models of hepatectomy, but the evidence in partial liver transplantation (LT) is lacking. In this study, a rat model of partial LT was used, and the impact of thrombopoietin‐induced perioperative thrombocytosis on graft regeneration, I/R injury and survival was investigated. In experiment I, 30% partial LT was performed. Under thrombocytosis, SFSS was attenuated, as shown by decreased levels of serum aminotransferases, bilirubin and ascites. Serum hepatocyte regeneration‐related cytokines, including insulin‐like growth factor‐1, hepatocyte growth factor, interleukin‐6 (IL‐6) and tumor necrosis factor‐α (TNF‐α), were elevated. Additionally, the proliferative signaling pathways, Ki67‐labeling index, PCNA‐labeling index, mitotic index and liver/body weight ratio were increased under thrombocytosis. The platelet‐induced regeneration was independent of thrombopoietin, as increases in the Ki67‐labelling and PCNA‐labelling indexes were abolished after reducing platelet counts by anti‐platelet serum in rats administered with thrombopoietin. For I/R injury, thrombocytosis did not aggravate oxidative stress, downstream signaling pathways, necrosis or apoptosis in the graft. After Kupffer cell depletion, the platelet‐induced attenuation of serum aminotransferases, increased serum levels of IL‐6 and TNF‐α, and proliferation‐related signaling pathways were abolished. Moreover, platelet accumulation in the graft decreased substantially. In experiment II, 20% partial LT was performed, and thrombocytosis improved postoperative survival. In conclusion, our results suggested that thrombocytosis stimulated graft regeneration and prolonged survival without aggregating I/R injury after partial LT, and Kupffer cells vitally contributed to platelet‐derived regeneration. Platelet therapies to increase perioperative platelet counts may improve the outcomes after LDLT
