Platelets Stimulate Liver Regeneration in a Rat Model of Partial Liver Transplantation

Abstract

Living donor liver transplantation (LDLT) is sometimes associated with impaired regeneration and severe ischemia/reperfusion injury (IRI) 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 (TPO)-induced perioperative thrombocytosis on graft regeneration, IRI, and survival was investigated. In experiment 1, a 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 (IL6), and tumor necrosis factor α (TNF-α), were elevated. In addition, the proliferative signaling pathways, Ki-67-labeling index, proliferating cell nuclear antigen (PCNA)-labeling index, mitotic index, and liver/body weight ratio were increased under thrombocytosis. The platelet-induced regeneration was independent of TPO because increases in the Ki-67-labeling and PCNA-labeling indexes were eliminated after reducing platelet counts by antiplatelet serum in rats administered with TPO. For IRI, thrombocytosis did not aggravate oxidative stress or downstream signaling pathways, necrosis, or apoptosis in the graft. After Kupffer cell (KC) depletion, the platelet-induced attenuation of serum aminotransferases, increased serum levels of IL6 and TNF-α, and proliferation-related signaling pathways were eliminated. Moreover, platelet accumulation in the graft decreased substantially. In experiment 2, a 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 IRI after partial LT, and KCs vitally contributed to platelet-derived regeneration. Platelet therapies to increase perioperative platelet counts may improve the outcomes after LDLT.

Role of the immune system in liver transplantation and its implications for therapeutic interventions

“…Additionally, other innate immune cells, including NKT cells, especially the Valpha14 NKT cell subtype, have been recognized for their role in immune tolerance following infusion 208 . In IRI, platelets are influenced by the inflammatory mediators released by KCs, resulting in the release of IL‐6, platelet‐activating factors, growth factors, TGF‐β, and other cytokines that contribute to the advancement of inflammation 209–211 . Peritoneal macrophages with the F4/80 hi GATA6 + LMP phenotype have been observed to migrate to the injury site and contribute to liver repair in experimental models of acute liver injury 212 …”

Dualistic role of platelets in living donor liver transplantation: Are they harmful?

“…LSECs and KCs were also reported to interact with platelets to stimulate liver regeneration. It was identified that platelets induced the release of IL-6 from LSECs through direct contact with LSECs[ 61 ]. On the other hand, platelets could attach to KCs, and the hepatic expression of TNF-α and IL-6, which are predominantly produced by KCs, increased in response to the interaction between platelets and KCs[ 62 ].…”

“…Although the positive role of higher perioperative platelet counts has been suggested, the precise mechanisms clarifying how platelets interact with other cells under I/R conditions were reported recently. Liang et al [ 61 ] reported that TPO-induced preoperative thrombocytosis contributed to a better outcome in a rat model of partial LT. In this study, platelets stimulated liver regeneration after partial LT via several proliferation-related cytokines and pathways.…”

“…The Akt signaling pathway, which could be activated by IGF-1[ 59 ], was reported to suppress TNF-α-mediated apoptosis through NF-κB activation[ 78 , 79 ]. It was supposed that the elevated secretion of IGF-1 under thrombocytosis enhanced the phosphorylation of Akt and NF-κB and consequently prevented liver grafts from undergoing apoptosis[ 61 ]. However, direct evidence proving the interaction between the Akt pathway and IGF-1 or TNF-α was not provided in previous studies.…”

Mouse Models of Liver Parenchyma Injuries and Regeneration

“…Both models are representative of findings in patients. The partial hepatectomy model simulates natural progression after hepatectomy surgery in patients with various liver diseases and explores novel therapeutic measures and enhance the recovery after hepatectomy, but also provide a more effective and safe guidance program for living donor liver transplantation ( Nojima et al, 2016 ; Liang et al, 2021 ). The CCl4 model simulates conditions for patients subjected to toxins, to radiation or having viral infections that target the pericentral (polyploid) cells.…”