Nguyen-Lefebvre Anh Thu, Selzner Nazia, Wrana Jeffrey L, Bhat Mamatha
Department of Medicine, Multi-Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada.
Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
FASEB J. 2021 May;35(5):e21570. doi: 10.1096/fj.202002284RR.
The liver is the only visceral organ in the body with a tremendous capacity to regenerate in response to insults that induce inflammation, cell death, and injury. Liver regeneration is a complicated process involving a well-orchestrated activation of non-parenchymal cells in the injured area and proliferation of undamaged hepatocytes. Furthermore, the liver has a Hepatostat, defined as adjustment of its volume to that required for homeostasis. Understanding the mechanisms that control different steps of liver regeneration is critical to informing therapies for liver repair, to help patients with liver disease. The Hippo signaling pathway is well known for playing an essential role in the control and regulation of liver size, regeneration, stem cell self-renewal, and liver cancer. Thus, the Hippo pathway regulates dynamic cell fates in liver, and in absence of its downstream effectors YAP and TAZ, liver regeneration is severely impaired, and the proliferative expansion of liver cells blocked. We will mainly review upstream mechanisms activating the Hippo signaling pathway following partial hepatectomy in mouse model and patients, its roles during different steps of liver regeneration, metabolism, and cancer. We will also discuss how targeting the Hippo signaling cascade might improve liver regeneration and suppress liver tumorigenesis.
肝脏是人体唯一的内脏器官，具有在遭受引发炎症、细胞死亡和损伤的刺激时进行大量再生的能力。肝脏再生是一个复杂的过程，涉及受损区域非实质细胞的精心激活以及未受损肝细胞的增殖。此外，肝脏有一个肝稳态调节机制，即其体积会根据内环境稳态所需进行调整。了解控制肝脏再生不同步骤的机制对于指导肝脏修复治疗、帮助肝病患者至关重要。河马信号通路在控制和调节肝脏大小、再生、干细胞自我更新以及肝癌方面发挥着重要作用，这是广为人知的。因此，河马信号通路调节肝脏中的动态细胞命运，在缺乏其下游效应分子YAP和TAZ的情况下，肝脏再生会严重受损，肝细胞的增殖扩张也会受阻。我们将主要综述在小鼠模型和患者中部分肝切除术后激活河马信号通路的上游机制、其在肝脏再生、代谢和癌症不同步骤中的作用。我们还将讨论靶向河马信号级联反应如何可能改善肝脏再生并抑制肝脏肿瘤发生。
