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Reply:

We agree with Dr. Coombes and Dr. Syn that Hedgehog (Hh) signaling may be an important factor influencing liver regeneration, and in particular the development of the ductular reaction and progenitor cell expansion. We have not particularly assessed the Hh signaling in patients with alcoholic hepatitis. Studies have shown that hedgehog-responsive progenitor cells proliferate in liver injury and accumulate in humans with alcoholic liver disease correlating with disease severity.1, 2 This observation is particularly interesting because Hh signaling has been shown to participate in progenitor cell activation and proliferation in adults and to induce hepatoblast proliferation during embryogenesis, but has to be shut off to allow hepatoblast commitment and differentiation.3 These findings suggest that Hh signaling may be implicated in the accumulation of progenitor cells in the liver, promoting proliferation and preventing differentiation. Although inhibition of Hh signaling seems to reduce progenitor cell response and liver regeneration in animal models of liver injury, the role of these cells in liver regeneration is not yet completely understood, and the contribution of Hh-responsive progenitor cells to newly generated hepatocytes has not been elucidated. Further studies are warranted to elucidate this question.

The association of inflammation with progenitor cell proliferation has been described but has never been investigated in alcoholic hepatitis. We agree that inflammation and progenitor cell proliferation are key events in alcoholic hepatitis, thus its relationship should be specifically investigated. In our study it was not possible to investigate the inflammatory cell populations infiltrating the damaged liver, but the overall quantification of inflammatory cells by standard histological methods did not show a positive correlation with progenitor cell expansion and mortality.

The results of our study raise the question whether liver progenitor cell expansion is a marker of liver injury in acute-on-chronic conditions or the result of an inefficient liver regeneration attempt. The assessment of liver progenitor cell expansion and differentiation in human samples together with mechanistic studies in relevant animal models of liver injury will help in understanding the role of progenitor cells in liver regeneration and disease outcome and its contribution to liver repair.

References

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  • 1
    Jung Y, Brown KD, Witek RP, Omenetti A, Yang L, Vandongen M, et al. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 2008; 134: 15321543.
  • 2
    Sancho-Bru P, Altamirano J, Rodrigo-Torres D, Coll M, Millan C, Jose Lozano J, et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis [published online ahead of print January 25, 2012]. HEPATOLOGY doi: 10.1002/hep.25614.
  • 3
    Hirose Y, Itoh T, Miyajima A. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Exp Cell Res 2009; 315: 26482657.

Pau Sancho-Bru M.D.*, José Altamirano M.D.*, Ramon Bataller M.D.*, * Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.