Abstract
BackgroundAlcohol insult triggers complex events in the liver, promoting fibrogenic/inflammatory signals and in more advanced cases, aberrant matrix deposition. It is well accepted that the regenerative capacity of the adult liver is impaired during alcohol injury. The liver progenitor/stem cells have been shown to play an important role in liver regeneration -in response to various chronic injuries; however, the effects of alcohol on stem cell differentiation in the liver are not well understood.MethodsWe employed hepatic progenitor cells derived from hESCs to study the impact of ethanol on hepatocyte differentiation by exposure of these progenitor cells to ethanol during hepatocyte differentiation.ResultsWe found that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitor cells in a dose-dependent manner. There was also a moderate cell cycle arrest at G1/S checkpoint in the ethanol treated cells, which is associated with a reduced level of cyclin D1 in these cells. Ethanol treatment specifically inhibited the activation of the ERK but not JNK nor the p38 MAP signaling pathway. At the same time, the WNT signaling pathway was also reduced in the cells exposed to ethanol. Upon evaluating the effects of the inhibitors of these two signaling pathways, we determined that the Erk inhibitor replicated the effects of ethanol on the hepatocyte differentiation and attenuated the WNT/β-catenin signaling, however, inhibitors of WNT only partially replicated the effects of ethanol on the hepatocyte differentiation.ConclusionOur results demonstrated that ethanol negatively regulated hepatic differentiation of hESC-derived hepatic progenitors through inhibiting the MAPK/ERK signaling pathway, and subsequently attenuating the WNT signaling pathway. Thus, our finding provides a novel insight into the mechanism by which alcohol regulates cell fate selection of hESC-derived hepatic progenitor cells, and the identified pathways may provide therapeutic targets aimed at promoting liver repair and regeneration during alcoholic injury.
Highlights
The liver is the major location for the metabolism of ethanol, and alcoholic hepatitis and other forms of alcoholic liver disease (ALD) are major complications of chronic excessive ethanol intake [1,2]
The types and nomenclature of liver stem/progenitor cells are in some dispute, and differ in rodents and humans, there is some consensus that they evolve from bipotent stem cells that resides within the Canal of the Hering between the hepatocyte plate and bile duct
Liver specific transcription factor C/EBPa has been shown to play an important role in hepatocyte differentiation, and it was significantly reduced by ethanol at all tested concentrations as assessed by Quantitative RT-PCR (qRT-PCR), whereas the expression of HNF1a was markedly down-regulated by the ethanol treatment at 100 mM (Figure 1E)
Summary
The liver is the major location for the metabolism of ethanol, and alcoholic hepatitis and other forms of alcoholic liver disease (ALD) are major complications of chronic excessive ethanol intake [1,2]. At an early stage in the course of alcohol-induced liver injury, damaged hepatocytes can be replaced by the proliferation of adult hepatocytes. The types and nomenclature of liver stem/progenitor cells are in some dispute, and differ in rodents and humans, there is some consensus that they evolve from bipotent stem cells that resides within the Canal of the Hering between the hepatocyte plate and bile duct. These liver stem/progenitor cells are shown to give rise to both hepatocytes and cholangiocytes in response to various chronic injuries [3,4]. The liver progenitor/stem cells have been shown to play an important role in liver regeneration -in response to various chronic injuries; the effects of alcohol on stem cell differentiation in the liver are not well understood
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