Platelets stimulate liver regeneration in a rat model of partial liver transplantation.

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.