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Mechanisms of hepatic stellate cell activation

Nature Reviews Gastroenterology & Hepatology volume 14, pages 397–411 (2017)Cite this article

Subjects

Key Points

  • Activation of hepatic stellate cells (HSCs) into proliferative, fibrogenic myofibroblasts is well established as the central driver of hepatic fibrosis in experimental and human liver injury

  • A panoply of intracellular events and signals in all cellular compartments drive the activated phenotype of HSCs, and many of these represent potential targets for antifibrotic therapies

  • Extracellular signals converging upon HSCs to promote their activation include those originating from the extracellular matrix and stimuli from resident and infiltrating inflammatory cells

  • Emerging concepts in HSC activation focus on novel mediators and intracellular signals, as well as drivers of HSC inactivation, which collectively have generated a template for uncovering novel therapeutic targets

Abstract

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.

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Figure 1: Functions, features and phenotypes of HSCs in normal and diseased livers.
Figure 2: Signalling molecules and pathways involved in HSC activation.
Figure 3: Extracellular stimuli to HSC activation.

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Acknowledgements

The laboratory of S.L.F. is supported by NIH grant DK56621.

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Authors and Affiliations

  1. Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1123, New York, 10029, New York, USA

    Takuma Tsuchida & Scott L. Friedman

  2. Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, 335–8505, Saitama, Japan

    Takuma Tsuchida

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Both authors discussed the concepts and contributed to the content of the work. T.T. generated a first draft of the article and S.L.F. reviewed and edited the manuscript before submission.

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Correspondence to Scott L. Friedman.

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S.L.F. is a consultant to 3-V Biotherapeutics, Abbvie Pharmaceuticals, Angion Biomedica, Akarna Therapeutics, Blade Therapeutics, Blueprint medicines, Boehringer Ingelheim, Bristol Myers Squibb, Can-Fite Biopharma, Chemocentryx, Conatus, Daichi Sankyo, Debio Pharmaceuticals, Deerfield consulting, DeuteRx, DS Biosciences, Eli Lilly Pharmaceuticals, Enanta Pharmaceuticals, Exalenz Biosciences, Fibrogen, Fractyl Bioscience, Galectin Therapeutics, Galmed, Genfit, Genkyotex, Glycotest, Glympse Bio, GNI Group, Immune Pharmaceuticals, Intercept, Ironwood Pharmaceuticals, Isis Pharmaceuticals, Janssen Pharmaceuticals, Jecure Therapeutics, Madrigal Pharmaceuticals, Metacrine, Metagenix, Merck Pharmaceuticals, Nimbus Therapeutics, Nitto, Northern Biologics, Novartis, Ocera Therapeutics, Pfizer, Raptor Pharmaceuticals, Roche, RuiYi, Sandhill Medical Devices, Scholar Rock, Shire Pharmaceuticals, Synageva BioPharma, Takeda Pharmaceuticals, Teva Pharmaceuticals, Tobira Therapeutics, Tokai Pharmaceuticals, Viking Therapeutics and Zafgen. T.T. is an employee of Mitsubushi Tanabe Pharma, Japan.

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Tsuchida, T., Friedman, S. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14, 397–411 (2017). https://doi.org/10.1038/nrgastro.2017.38

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