Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans
Intrahepatic fibrin(ogen) deposition drives liver regeneration after partial hepatectomy in mice and humans
复制标题
DOI：
10.1182/blood-2018-08-869057
复制
发表时间：
2019-03-14
期刊：
影响因子：
20.3
通讯作者：
Luyendyk, James P.
中科院分区：
文献类型：
--
作者：
Groeneveld, Dafna;Pereyra, David;Luyendyk, James P.
啮齿动物和人类部分肝切除术后，血小板在刺激肝脏再生方面发挥着关键作用。当血小板受到抑制时，啮齿动物的肝脏再生会延迟。然而，血小板积累和促进肝再生的确切机制仍不清楚。最近报道了小鼠部分肝切除术（PHx）后凝血酶依赖性肝内纤维蛋白（原）沉积，但纤维蛋白（原）沉积在肝再生中的作用尚未研究。我们测试了纤维蛋白（原）通过促进肝内血小板积累促进肝再生的假设，并确定了 PHx 后快速肝内凝血的触发因素。野生型小鼠中的 PHx 引发快速肝内凝血，肝内纤维蛋白（原）沉积证明了这一点。在肝脏特异性组织因子缺乏的小鼠中，肝内纤维蛋白（原）沉积被消除，从而确定了 PHx 后凝血的触发因素。通过蛋白酶激活受体 4 直接凝血酶激活血小板并不会促进 PHx 后的肝细胞增殖，表明凝血酶主要通过驱动肝内纤维蛋白（原）沉积来促进肝再生。 ancrod 消耗纤维蛋白原可减少 PHx 后肝内血小板积累和肝细胞增殖，表明纤维蛋白（原）通过促进肝内血小板积累促进 PHx 后肝再生。与小鼠纤维蛋白（原）的保护功能一致，术后血浆纤维蛋白原水平低与肝切除患者的肝功能障碍和死亡率相关。此外，肝切除后患者的肝脏中肝内纤维蛋白（原）沉积明显增加，但在切除后表现出肝功能障碍的患者中明显不存在。结果表明，PHx 后凝血依赖性肝内纤维蛋白（原）沉积驱动血小板积累和肝再生的新机制。
Platelets play a pivotal role in stimulating liver regeneration after partial hepatectomy in rodents and humans. Liver regeneration in rodents is delayed when platelets are inhibited. However, the exact mechanisms whereby platelets accumulate and promote liver regeneration remain uncertain. Thrombin-dependent intrahepatic fibrin(ogen) deposition was recently reported after partial hepatectomy (PHx) in mice, but the role of fibrin(ogen) deposits in liver regeneration has not been investigated. We tested the hypothesis that fibrin(ogen) contributes to liver regeneration by promoting intrahepatic platelet accumulation and identified the trigger of rapid intrahepatic coagulation after PHx. PHx in wildtype mice triggered rapid intrahepatic coagulation, evidenced by intrahepatic fibrin(ogen) deposition. Intrahepatic fibrin(ogen) deposition was abolished in mice with liver-specific tissue factor deficiency, pinpointing the trigger of coagulation after PHx. Direct thrombin activation of platelets through protease-activated receptor-4 did not contribute to hepatocyte proliferation after PHx, indicating that thrombin contributes to liver regeneration primarily by driving intrahepatic fibrin(ogen) deposition. Fibrinogen depletion with ancrod reduced both intrahepatic platelet accumulation and hepatocyte proliferation after PHx, indicating that fibrin(ogen) contributes to liver regeneration after PHx by promoting intrahepatic platelet accumulation. Consistent with the protective function of fibrin(ogen) in mice, low postoperative plasma fibrinogen levels were associated with liver dysfunction and mortality in patients undergoing liver resection. Moreover, increased intrahepatic fibrin(ogen) deposition was evident in livers of patients after liver resection but was remarkably absent in patients displaying hepatic dysfunction postresection. The results suggest a novel mechanism whereby coagulation-dependent intrahepatic fibrin(ogen) deposition drives platelet accumulation and liver regeneration after PHx.