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Am J Physiol Gastrointest Liver Physiol 297: G451-G460, 2009. First published July 16, 2009; doi:10.1152/ajpgi.00055.2009
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LIVER AND BILIARY TRACT

Pathological roles of bone marrow-derived stellate cells in a mouse model of alcohol-induced fatty liver

Tatsuya Fujimiya,1,* Jinyao Liu,1,* Hideto Kojima,2 Seiko Shirafuji,1 Hiroshi Kimura,2 and Mineko Fujimiya3

1Department of Legal Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi; 2Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga; 3Department of Anatomy, Sapporo Medical University, Sapporo, Japan

Submitted 13 February 2009 ; accepted in final form 12 July 2009

Chronic alcohol consumption activates hepatic stellate cells (HSCs) and causes fatty degeneration in the liver. However, the origin of HSCs and the mechanism of fatty changes of the liver have not been fully elucidated. Here, we examined the roles of bone marrow-derived cells (BMDCs) in a mouse model with chronic alcohol consumption. We performed bone marrow transplantation from transgenic mice expressing green fluorescence protein (GFP) to female wild-type and ROSA mice (B6.129S7-Gt 26Sor/J, transgenic mice expressing β-galactosidase, β-gal) and treated them with ethanol (EtOH) for 8 or 16 wk. GFP-expressing BMDCs increased in the liver with EtOH treatment in a time-dependent manner. In response to excess alcohol consumption, {approx}68% of the BMDCs became activated HSCs in that they expressed {alpha}-smooth muscle actin. Meanwhile, {approx}67% and {approx}66% of these BMDCs expressed Tnf-{alpha} and transforming growth factor (Tgf)-β1, respectively, and the activities were further supported by the excessive mRNA expression of Tnf-{alpha} and Tgf-β1 in RT-PCR, respectively. Cell fusion occurs between BMDCs and nonparenchymal cells but scarcely occurs between BMDCs and hepatocytes, demonstrated by double staining of β-gal/GFP and further supported by the Y-chromosome staining. The EtOH withdrawal normalized most of the abnormalities produced by chronic alcohol consumption. These results indicate that excess alcohol consumption stimulates both the homing of HSCs from the bone marrow and their profibrogenic cytokine production in a mouse model of alcohol-induced fatty liver disease.

bone marrow transplantation; ethanol; liver fibrosis; hepatic stellate cell


Address for reprint requests and other correspondence: J. Liu, Dept. of Legal Medicine, Yamaguchi Univ. Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan (e-mail: czhliu{at}yamaguchi-u.ac.jp)






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