Potential conflict of interest: Nothing to report.
Hedgehog-responsive progenitors: Predictors of liver outcomes?†
Article first published online: 31 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 5, pages 2010–2011, November 2012
How to Cite
Coombes, J. and Syn, W.-K. (2012), Hedgehog-responsive progenitors: Predictors of liver outcomes?. Hepatology, 56: 2010–2011. doi: 10.1002/hep.25840
- Issue published online: 31 OCT 2012
- Article first published online: 31 OCT 2012
- Accepted manuscript online: 17 MAY 2012 11:22AM EST
- Manuscript Accepted: 16 MAR 2012
- Manuscript Received: 27 FEB 2012
Vol. 58, Issue 2, 838, Article first published online: 29 JAN 2013
To the Editor:
Sancho-Bru et al. reported that progenitor-cell expansion occurs during alcoholic hepatitis (AH).1 Critically, they observed that K7 and prominin-1 progenitors were independent predictors of 90-day mortality. Their findings are consistent with a previous study documenting the accumulation of Hedgehog (Hh)-responsive progenitors in humans and mice with alcoholic liver disease,2 and where the greatest number of Hh-responsive progenitors were detected in livers of patients with a high discriminant function (DF; >32).
Studies suggest that proinflammatory cytokines, growth factors, and morphogens such as Hh3 modulate the progenitor response. Hh ligands secreted by dying hepatocytes directly trigger proliferation of progenitor cells. It is likely that the worse the injury or death, the greater the amount of Hh ligand secreted. In turn, this leads to a more pronounced progenitor response. Hh also induces reprogramming of progenitors to fibroblasts and promotes the transition of quiescent hepatic stellate cells to activated myofibroblasts. Thus, resurrection of Hh signaling could explain the observed correlation of K7 with MELD and DF.1 Given the importance of Hh in the repair-inflammatory response, it is surprising that the degree of inflammation did not correlate with progenitor response or outcome. It is possible that immunohistochemistry could have underestimated the size of the inflammatory response, and flow cytometry of total liver tissues would have been more accurate if available. As Hh modulates sinusoidal endothelial function, it would be critical to ascertain if Hh pathway activation regulates leukocyte subset recruitment and therefore dictates liver outcomes.
The observation that K7+ cells are found in patients with the highest mortality questions the role of the progenitor response. Is it simply a bystander effect of injury (marker of injury), an ineffectual attempt at liver repair, or both? Inhibition of the Hh pathway in a mouse model of chronic injury led to an attenuated progenitor response and reduced fibrosis,4 whereas blockade during acute liver injury resulted in a blunted progenitor response, impaired liver regeneration, and reduced survival,5 suggesting that progenitors play a pivotal role in liver repair. Indeed, authors in this study noted that high levels of EpCAM-expressing progenitors may lead to improved outcomes after AH. Future studies will need to address the functional capacity of liver progenitor subsets.
- 1Liver 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., , , , , , et al.
- 2Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 2008; 134: 1532–1543., , , , , , et al.
- 3The role of Hedgehog signaling in fibrogenic liver repair. Int J Biochem Cell Biol 2011; 43: 238–244., , , .
- 4Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease. Gastroenterology 2009; 137: 1478–1488.e8., , , , , , et al.
- 5Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice. HEPATOLOGY 2010; 51: 1712–1723., , , , , , et al.
Jason Coombes M.D.*, Wing-Kin Syn M.D.*, * Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham, United Kingdom.