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  • Review Article
  • Published:

Liver regeneration — mechanisms and models to clinical application

Nature Reviews Gastroenterology & Hepatology volume 13, pages 473–485 (2016)Cite this article

Subjects

Key Points

  • Liver regeneration occurs efficiently in the normal liver to restore architecture, size and function; chronic injury severely impairs liver regeneration through excess inflammation, scarring and epithelial abnormalities, and is less well-studied but clinically important

  • New experimental models are emerging; zebrafish are an excellent new tool to study liver regeneration and enable large-scale chemical screening assays

  • A gap exists between current animal models of liver regeneration and clinically important scenarios of severe liver injury and impaired liver regeneration

  • Understanding and promoting regeneration and repair of the failing liver is a key challenge of major clinical importance

  • Modern imaging techniques will enable noninvasive real-time assessment of liver structure and function

  • Cell therapies that have been successful in animal models are now being trialled in the more challenging clinical arena

Abstract

Liver regeneration has been studied for many decades and the mechanisms underlying regeneration of the normal liver following resection or moderate damage are well described. A large number of factors extrinsic (such as bile acids and circulating growth factors) and intrinsic to the liver interact to initiate and regulate liver regeneration. Less well understood, and more clinically relevant, are the factors at play when the abnormal liver is required to regenerate. Fatty liver disease, chronic scarring, prior chemotherapy and massive liver injury can all inhibit the normal programme of regeneration and can lead to liver failure. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or directly stimulate liver regeneration. Although animal models of liver regeneration have been highly instructive, the clinical relevance of some models could be improved to bridge the gap between our in vivo model systems and the clinical situation. Likewise, modern imaging techniques such as spectroscopy will probably improve our understanding of whole-organ metabolism and how this predicts the liver's regenerative capacity. This Review describes briefly the mechanisms underpinning liver regeneration, the models used to study this process, and discusses areas in which failed or compromised liver regeneration is clinically relevant.

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Figure 1: Animal models of liver regeneration.
Figure 2: Schematic of normal and abnormal liver regeneration.
Figure 3: Strategies to improve liver regeneration.

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Acknowledgements

This paper presents independent research supported by the Birmingham National Institute for Health Research (NIHR) Liver Biomedical Research Unit based at the University Hospital Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. P.N.N. is supported by the NIHR Biomedical Research Unit.

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  1. MRC Centre for Regenerative Medicine, 5 Little France Drive, University of Edinburgh, Edinburgh, EH16 4UU, UK

    Stuart J. Forbes

  2. Birmingham National Institute for Health Research (NIHR) Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Vincent Drive, Birmingham, B15 2TT, UK

    Philip N. Newsome

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Both authors contributed equally to all aspects of this manuscript.

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Correspondence to Stuart J. Forbes.

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Forbes, S., Newsome, P. Liver regeneration — mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 13, 473–485 (2016). https://doi.org/10.1038/nrgastro.2016.97

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