Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1123, New York, New York 10029, USA.
Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397-411. doi: 10.1038/nrgastro.2017.38. Epub 2017 May 10.
Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) - transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myofibroblasts - is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.
肝纤维化是一种动态过程，其特征是由于任何病因（包括病毒感染、酒精性肝病和 NASH）引起的慢性肝损伤导致细胞外基质的净积累。肝星状细胞（HSCs）的激活-静止的、储存维生素 A 的细胞向增殖性、纤维生成性肌成纤维细胞的转分化-现已被充分确立为实验性和人类肝损伤中纤维化的主要驱动因素。然而，包括自噬、内质网应激、氧化应激、视黄醇和胆固醇代谢、表观遗传学和受体介导的信号在内的新途径和介质的不断发现，揭示了 HSC 激活的复杂性。包括巨噬细胞、肝细胞、肝窦内皮细胞、自然杀伤细胞、自然杀伤 T 细胞、血小板和 B 细胞在内的驻留细胞和炎症细胞的细胞外信号进一步调节 HSC 的激活。最后，HSC 清除途径已得到极大澄清，包括凋亡、衰老和恢复到无活性状态。总之，这些发现强化了 HSC 激活的显著复杂性和可塑性，并强调了阐明其调控的重要性，以期推进肝病新诊断和治疗方法的发展。
