肝再生：生物学和病理学机制及其意义

StephenW

    Review Article
    Published: 06 August 2020

Liver regeneration: biological and pathological mechanisms and implications

    George K. Michalopoulos & Bharat Bhushan

Nature Reviews Gastroenterology & Hepatology (2020)Cite this article

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Abstract

The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this ‘hepatostat’ will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver.
Key points

    Hepatocyte proliferation during liver regeneration is controlled by multiple extracellular signals, two of which (MET and EGFR) are directly mitogenic and others only delay liver regeneration if they are bypassed.

    Intracellular signalling pathways in hepatocytes are very rapidly (within minutes) activated after partial hepatectomy. The mechanisms triggering these pathways are not clear.

    All hepatic cell types participate in cell proliferation during liver regeneration. No ‘stem cells’ are involved.

    If hepatocyte or cholangiocyte proliferation is seriously impaired, then each of the two cell types can transdifferentiate into the other and function as a facultative stem cell.

    Loss of hepatocytes occurring in chronic liver diseases triggers compensatory proliferation of the surviving hepatocytes and exposes them to potentially genotoxic injury that might lead to neoplasia.

StephenW

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    发布时间：2020年8月6日

肝再生：生物学和病理学机制及其意义

    乔治·米哈洛普洛斯（George K. Michalopoulos）和巴拉特·巴拉山（Bharat Bhushan）

《自然评论》胃肠病和肝病（2020）

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抽象

肝脏是唯一使用再生机制来确保肝脏与体重之比始终保持体内稳态所需能量的100％的实体器官。其他实体器官（例如肺，肾和胰腺）会根据组织损失进行调整，但不会恢复到正常的100％。这篇“ hepatostat”背后的再生途径的最新知识将在本综述中介绍。急性损伤引起的肝脏再生始终是有益的，并且已得到广泛研究。涉及部分肝切除或化学损伤的实验模型揭示了细胞外和细胞内信号通路，这些通路可将肝脏恢复至与损伤前相同的大小和重量。另一方面，在任何病因的慢性肝病中都可能发生的肝细胞慢性丢失，通常会产生不良后果，包括纤维化，肝硬化和肝肿瘤。肝细胞和胆管细胞的再生活性通常以表型保真度为特征。但是，当两种细胞类型之一的再生失败时，肝细胞和胆管细胞将作为兼职干细胞发挥作用，并相互分化为正常肝结构。肝再定殖模型已证明肝细胞具有无限的再生能力。但是，在正常肝脏中，细胞更新非常缓慢。静息肝小叶的所有区域都与正常肝中肝细胞和胆管细胞群的维持具有同等意义。
关键点

    肝脏再生过程中的肝细胞增殖受多种细胞外信号控制，其中两个信号（MET和EGFR）直接促有丝分裂，其他信号如果绕开则仅延迟肝脏再生。

    肝部分切除后，肝细胞内的细胞内信号传导途径非常迅速（几分钟内）被激活。触发这些途径的机制尚不清楚。

    所有肝细胞类型均在肝再生过程中参与细胞增殖。不涉及“干细胞”。

    如果肝细胞或胆管细胞的增殖受到严重损害，则两种细胞中的每一种都可以分化为另一种，并起兼性干细胞的作用。

    在慢性肝病中发生的肝细胞损失会触发尚存的肝细胞的代偿性增殖，并使它们暴露于可能导致肿瘤形成的潜在遗传毒性损伤中。