Hedgehog-responsive progenitors: Predictors of liver outcomes?



This article is corrected by:

  1. Errata: Correction Volume 58, Issue 2, 838, Article first published online: 29 January 2013

  • Potential conflict of interest: Nothing to report.

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.

Jason Coombes M.D.*, Wing-Kin Syn M.D.*, * Queen Elizabeth Hospital, University Hospital Birmingham NHS Trust, Birmingham, United Kingdom.