Alcohol Disrupts Human Liver Stem/Progenitor Cell Proliferation and Differentiation
|Xin Shi1, Chia-Cheng Chang2, Marc D Basson1, AruuLl Uyhaa2, Lixin Wei3 and Ping Zhang1*|
|1Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA|
|2Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA|
|3Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China|
|Corresponding Author :||Ping Zhang
Professor of Surgery, Pharmacology and Toxicology
Department of Surgery, Michigan State University College of Human Medicine
B203B Life Science Building, 1355 Bogue Street
East Lansing, Michigan 48824, USA
Tel: (517) 884-6843
Fax: (517) 432-2310
E-mail: [email protected]
|Received April 02, 2014; Accepted May 10, 2014; Published May 12, 2014|
|Citation: Shi X, Chang CC, Basson MD, Upham BL, Wei L, Zhang P (2014) Alcohol Disrupts Human Liver Stem/Progenitor Cell Proliferation and Differentiation. J Stem Cell Res Ther 4:205. doi:10.4172/2157-7633.1000205|
|Copyright: © 2014 Shi X, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
Objective: Excessive alcohol consumption injures the liver resulting in various liver diseases including liver cirrhosis. Advanced liver disease continues to be a major challenge to human health. Liver stem/progenitor cells (LSPCs) are tissue specific precursors with a distinct capacity of multi-lineage differentiation. These precursor cells may play an important role in the process of tissue injury repair and pathological transition of liver structures. At the present time, knowledge about the effect of alcohol on LSPC function during the development of alcoholic liver disease remains absent. This study was conducted to investigate changes in LSPC activity of proliferation and differentiation following alcohol exposure. The disruption of cell signaling mechanisms underlying alcohol-induced alteration of LSPC activities was also examined.
Methods: Primary and immortalized human liver stem cells (HL1-1 cells and HL1-hT1 cells, respectively) were cultured in media optimized for cell proliferation and hepatocyte differentiation in the absence and presence of ethanol. Changes in cell morphology, proliferation and differentiation were determined. Functional disruption of cell signaling components following alcohol exposure was examined.
Results: Ethanol exposure suppressed HL1-1 cell growth [as measured by cell 5-bromo-2-deoxyuridine (BrdU) incorporation] mediated by epidermal growth factor (EGF) or EGF plus interleukin-6 (IL-6) in an ethanol dosedependent manner. Similarly, ethanol inhibited BrdU incorporation into HL1-hT1 cells. Cyclin D1 mRNA expression by HL1-hT1 cells was suppressed when cells were cultured with 50 and 100 mM ethanol. Ethanol exposure induced morphological change of HL1-1 cells toward a myofibroblast-like phenotype. Furthermore, ethanol downregulated E-cadherin expression while increasing collagen I expression by HL1-1 cells. Ethanol also stimulated Snail transcriptional repressor (Snail) and α-smooth muscle actin (α-SMA) gene expression by HL1-1 cells. Conclusion: These results demonstrate that the direct effect of alcohol on LSPCs is inhibiting their proliferation and promoting mesenchymal transition during their differentiation. Alcohol interrupts LSPC differentiation through interfering Snail signaling.