Mini review
New insights into liver regeneration

https://doi.org/10.1016/j.clinre.2011.04.002Get rights and content

Summary

Even if the Greeks probably anticipated rather than discovered the extraordinary regenerative capacity of the liver with the Prometheus myth, this phenomenon still fascinates scientists nowadays with the same enthusiasm. There are good reasons to decipher this process other than to find an answer to our fantasy of immortality: it could indeed help patients needing large liver resections or living-donor liver transplantation, it could increase our understanding of liver pathology and finally it could enable novel cell-therapy approaches. For decades, most of our knowledge about the mechanisms involved in liver regeneration came from the classic two-thirds partial hepatectomy (PH) model. In this scenario, hepatocytes play the leading role, which raises the question of the simple existence of a stem cell population. Recently however, hepatic progenitor cells come again under the limelight, seeming to play a role in liver physiology and in various liver diseases such as steatosis or cirrhosis. Excellent reviews have recently addressed liver regeneration. Our goal is therefore to focus on recent improvements in the field, highlighting data mostly published in the last two years in order to draw a putative picture of what the future research axes on liver regeneration might look like.

Section snippets

Liver regeneration after partial hepatectomy (PH): and the winner is… the hepatocyte!

After a two-thirds partial hepatectomy (PH) in rodents, the remnant liver lobes will compensate for lost tissue and recover the initial liver mass in less than two weeks [1]. In studying this model, the first surprise came from the discovery that near all hepatocytes, which are quiescent and differentiated cells in the adult resting liver, are the first cells to re-enter the cell cycle rapidly after PH [2]. Serial transplantation experiments in rodents have shown that adult hepatocytes have a

Oval cells, small hepatocyte progenitor cells, intermediate hepatobiliary cells: different facets for a same character?

In the fifties, Opie and Farber described a category of small hepatic cells that they called oval cells, emerging from the canal of Hering, where bile canaliculi connect with bile ducts. Since then, it has become a hackneyed term used to define a highly heterogeneous population of cells whose fate is classically bipotent giving rise to both hepatocytes and cholangiocytes at least in vitro and at least in rodents. The search for oval cells origin led to propose that mesenchymal or stellate cells

Conclusion

Although we thought that the main molecular pathways involved in liver regeneration after partial hepatectomy were already deciphered, the last few years have yet brought new insights into mechanisms involved in this process. These emerging and sometimes surprising results foreshadow the likely research priorities for the next coming years: a better understanding of the role played by the environment and by progenitor cells in liver repair depending on the disease, a consensual phenotypical

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgements

H. Gilgenkrantz’ group is supported by INSERM, CNRS, université Paris-Descartes, ANR and INCA. A special thanks goes to C. Mitchell for the critical reading of this manuscript and to N. Fausto whose work and reviews are ever a source of inspiration…

References (68)

  • N.L. Bucher

    Regeneration of mammalian liver

    Int Rev Cytol

    (1963)
  • N.L. Bucher

    Liver regeneration: an overview

    J Gastroenterol Hepatol

    (1991)
  • K. Overturf et al.

    Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes

    Am J Pathol

    (1997)
  • G. Zajicek et al.

    The streaming liver

    Liver

    (1985)
  • G. Zajicek et al.

    The streaming liver. V: time and age-dependent changes of hepatocyte DNA content, following partial hepatectomy

    Liver

    (1989)
  • M.P. Bralet et al.

    Cell lineage study in the liver using retroviral mediated gene transfer. Evidence against the streaming of hepatocytes in normal liver

    Am J Pathol

    (1994)
  • S. Kennedy et al.

    Experiments in transgenic mice show that hepatocytes are the source for postnatal liver growth and do not stream

    Hepatology

    (1995)
  • E. Seki et al.

    Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration

    Hepatology

    (2005)
  • M. Lesurtel et al.

    Platelet-derived serotonin mediates liver regeneration

    Science

    (2006)
  • N. Fausto et al.

    Liver regeneration

    Hepatology

    (2006)
  • M.U. Latasa et al.

    Delayed liver regeneration in mice lacking liver serum response factor

    Am J Physiol Gastrointest Liver Physiol

    (2007)
  • J. Li et al.

    Relationships between deficits in tissue mass and transcriptional programs after partial hepatectomy in mice

    Am J Pathol

    (2009)
  • V. Gazit et al.

    Liver regeneration is impaired in lipodystrophic fatty liver dystrophy mice

    Hepatology

    (2010)
  • E. Shteyer et al.

    Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice

    Hepatology

    (2004)
  • E.P. Newberry et al.

    Altered hepatic triglyceride content after partial hepatectomy without impaired liver regeneration in multiple murine genetic models

    Hepatology

    (2008)
  • A. Natarajan et al.

    receptor is required for efficient liver regeneration

    Proc Natl Acad Sci U S A

    (2007)
  • S. Paranjpe et al.

    RNA interference against hepatic epidermal growth factor receptor has suppressive effects on liver regeneration in rats

    Am J Pathol

    (2010)
  • V.M. Factor et al.

    Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice

    PLoS One

    (2010)
  • C. Torre et al.

    The Transforming Growth Factor-alpha and cyclin D1 genes are direct targets of beta-catenin signaling in hepatocyte proliferation

    J Hepatol

    (2010)
  • K.J. Riehle et al.

    Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3

    J Exp Med

    (2008)
  • S. Haga et al.

    Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice

    J Hepatol

    (2005)
  • M.M. Goggin et al.

    Rapamycin-sensitive induction of eukaryotic initiation factor 4F in regenerating mouse liver

    Hepatology

    (2004)
  • S. Haga et al.

    The survival pathways phosphatidylinositol-3 kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation

    Hepatology

    (2009)
  • J. Romero-Gallo et al.

    Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy

    Oncogene

    (2005)
  • S. Oe et al.

    Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice

    Hepatology

    (2004)
  • A. Thenappan et al.

    Role of transforming growth factor beta signaling and expansion of progenitor cells in regenerating liver

    Hepatology

    (2010)
  • C. Meijer et al.

    Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy

    Liver

    (2000)
  • L. Atzori et al.

    Hepatic stellate cell: a star cell in the liver

    Int J Biochem Cell Biol

    (2009)
  • A.V. Tumanov et al.

    T cell-derived lymphotoxin regulates liver regeneration

    Gastroenterology

    (2009)
  • R. Sun et al.

    Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma)

    Gastroenterology

    (2004)
  • H. Nakashima et al.

    Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy

    Gastroenterology

    (2006)
  • Z. Dong et al.

    Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice

    Hepatology

    (2007)
  • K. Matsumoto et al.

    Liver organogenesis promoted by endothelial cells prior to vascular function

    Science

    (2001)
  • B.S. Ding et al.

    Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration

    Nature

    (2010)

    • Cited by (48)

    • Signaling pathways of liver regeneration: Biological mechanisms and implications

      2024, iScience

    • 3D Bioprinting for Liver Regeneration

      2022, 3D Bioprinting and Nanotechnology in Tissue Engineering and Regenerative Medicine

    • Vanillin augments liver regeneration effectively in hioacetamide induced liver fibrosis rat model

      2021, Life Sciences
      Citation Excerpt :

      Liver has a substantial potential to regenerate after tissue loss [38]. However, severe and persistent exposure to hepato-toxic drugs without medical intervention causes liver fibrosis induction and liver regeneration impairment with pronounced decrease in hepatic cells proliferation, leading to liver cirrhosis and organ failure eventually [39]. Though liver transplantation is the most appropriate solution for liver cirrhotic patients, it is an improbable option for most patients due to shortage of donors.

    • The potential diagnostic and therapeutic applications of exosomes in drug-induced liver injury

      2021, Toxicology Letters

    • Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine

      2018, American Journal of Pathology

    • Regulatory signatures of liver regeneration distilled by integrative analysis of mRNA, histone methylation, and proteomics

      2017, Journal of Biological Chemistry
      Citation Excerpt :

      The method of partial hepatectomy (PH) was described by Higgins and Anderson in 1931 (6) and has been widely applied to the study of liver regeneration. Although more and more knowledge has been accumulated about the liver regeneration after PH (7–9), this model may only clarify the mechanism of postoperative liver regeneration (10). On the other hand, the molecular mechanism by which PVE leads to compensatory hypertrophy of the liver remains largely unclear.

    View all citing articles on Scopus
    View full text
    Copyright © 2011 Elsevier Masson SAS. All rights reserved.