肝臟再生：生物學和病理學機制及其意義

StephenW

Liver regeneration: biological and pathological mechanisms and implications

    George K. Michalopoulos & Bharat Bhushan

Nature Reviews Gastroenterology & Hepatology volume 18, pages40–55(2021)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

肝臟再生：生物學和病理學機制及其意義

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

《自然評論》胃腸病和肝病，第18卷，第40–55（2021）頁，引用本文

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抽象

肝臟是唯一使用再生機制確保肝臟與體重之比始終保持體內穩態所需能量100％的實體器官。其他實體器官（如肺，腎和胰腺）會根據組織損失進行調整，但不會恢復到正常的100％。這篇“ hepatostat”背後的再生途徑的最新知識將在本綜述中介紹。急性損傷引起的肝再生始終是有益的，並且已得到廣泛研究。涉及部分肝切除或化學損傷的實驗模型揭示了細胞外和細胞內信號通路，這些通路可將肝臟恢復至與損傷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發生的肝細胞慢性丟失，通常會產生不良後果，包括纖維化，肝硬化和肝腫瘤。肝細胞和膽管細胞的再生活性通常以表型保真度為特徵。但是，當兩種細胞類型之一的再生失敗時，肝細胞和膽管細胞將作為兼職幹細胞發揮作用，並相互分化，以恢復正常的肝臟結構。肝再定殖模型已證明肝細胞具有無限的再生能力。但是，在正常肝臟中，細胞更新非常緩慢。靜息肝小葉的所有區域都與正常肝中肝細胞和膽管細胞群的維持具有同等意義。
關鍵點

    肝臟再生過程中的肝細胞增殖受多種細胞外信號控制，其中兩個信號（MET和EGFR）直接促有絲分裂，其他信號如果繞開則僅延遲肝臟再生。

    肝部分切除後，肝細胞內的細胞內信號傳導途徑被迅速激活（數分鐘之內）。觸發這些途徑的機制尚不清楚。

    所有肝細胞類型均在肝再生過程中參與細胞增殖。不涉及“幹細胞”。

    如果肝細胞或膽管細胞的增殖受到嚴重損害，則兩種細胞中的每一種都可以分化為另一種，並起兼性幹細胞的作用。

    在慢性肝病中發生的肝細胞損失會觸發尚存的肝細胞的代償性增殖，並使它們暴露於可能導致腫瘤形成的潛在遺傳毒性損傷中。