Role of the Hippo pathway in liver regeneration and repair: recent advances.

IF 5 3区 医学 Q2 IMMUNOLOGY Inflammation and Regeneration Pub Date : 2022-12-05 DOI:10.1186/s41232-022-00235-5
Monica Pibiri, Gabriella Simbula
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引用次数: 5

Abstract

Although the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These "abnormal livers" have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during "normal healthy liver regeneration" (i.e., in a normal liver after 2/3 partial hepatectomy) and "abnormal liver regeneration" (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells.

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Hippo通路在肝脏再生和修复中的作用:最新进展。
尽管参与正常肝脏再生的信号通路已经被很好地表征,但对慢性组织损伤影响的肝脏的研究却很少。这些“异常肝脏”的再生反应受损,导致肝脏修复和纤维化。肿瘤抑制因子Hippo通路在肝脏再生和修复中起关键作用。在此基础上,本文综述了近期关于Hippo信号通路参与“正常健康肝脏再生”(即2/3肝部分切除后的正常肝脏)和“异常肝脏再生”(即慢性疾病损伤的肝脏)的研究。对于旨在改善受损肝脏再生反应的新疗法而言,这可能是一个需要解决的重要问题。本文报道的研究表明,在正常肝脏再生过程中,Hippo共激活因子YAP/TAZ的激活通过直接BEC增殖或/和肝细胞去分化为可转分化为BECs的HPCs,促进了新的胆管网络的形成。此外,YAP/TAZ信号通路与其他信号通路的相互作用介导Kupffer细胞的募集和激活,Kupffer细胞为实质细胞和/或非实质细胞释放有丝分裂细胞因子,并参与细胞碎片的吞噬。此外,yap介导的星状细胞(hsc)激活通过合成细胞外基质促进肝脏再生。然而,在慢性疾病肝脏中,当超过肝脏再生的预定阈值时,YAP/TAZ激活导致以肝纤维化为特征的修复过程。在这种情况下,实质细胞和非实质细胞中的YAP/TAZ激活导致(i)静止hsc分化为肌成纤维hsc;(ii)巨噬细胞募集,释放炎性细胞因子;(iii)巨噬细胞向M2表型极化。由于慢性肝损伤中受损肝细胞的积累是肝癌发展的一个重要危险因素,本综述还讨论了Hippo通路在清除受损细胞中的作用。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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