Pathological roles of bone marrow-derived stellate cells in a mouse model of alcohol-induced fatty liver.
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 beta-galactosidase, beta-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, approximately 68% of the BMDCs became activated HSCs in that they expressed alpha-smooth muscle actin. Meanwhile, approximately 67% and approximately 66% of these BMDCs expressed Tnf-alpha and transforming growth factor (Tgf)-beta1, respectively, and the activities were further supported by the excessive mRNA expression of Tnf-alpha and Tgf-beta1 in RT-PCR, respectively. Cell fusion occurs between BMDCs and nonparenchymal cells but scarcely occurs between BMDCs and hepatocytes, demonstrated by double staining of beta-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.
Fujimiya
Tatsuya
T
Department of Legal Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Liu
Jinyao
J
Kojima
Hideto
H
Shirafuji
Seiko
S
Kimura
Hiroshi
H
Fujimiya
Mineko
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D000199:Actins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase