Antifibrotic effect of hepatocyte growth factor-expressing mesenchymal stem cells in small-for-size liver transplant rats.
Ischemia-reperfusion and chronic injuries associated with small-for-size liver transplantation (SFSLT) impair the regeneration of liver graft and induce liver fibrosis. Mesenchymal stem cells (MSCs) can prevent the development of liver fibrosis, and hepatocyte growth factor (HGF) can also attenuate liver cirrhosis. Our previous studies have demonstrated that higher occurrence of liver fibrosis existed in rats post-SFSLT, and that implantation of HGF/MSCs, the human HGF (hHGF)-expressing MSCs, can improve liver regeneration, reduce mortality of rats, as well as have the potent antifibrotic effect in this SFSLT model. In the present study, we implanted HGF/MSCs into liver grafts via the portal vein and investigated their role in antifibrosis effect, using a 30% SFSLT rat model. Fibrosis indexes, including laminin (LN), hyaluronic acid (HA) levels in serum and hydroxyproline (Hyp) content in the liver grafts, the expression of transforming growth factor-beta1 (TGF-beta(1)), rat HGF (rHGF), alpha-smooth muscle actin (alpha-SMA) in hepatic stellate cells (HSCs), alanine aminotransferase (ALT), total bilirubin (BIL), and albumin (ALB) levels in serum, in rats in different treatment groups were assessed at different time points. We found that HGF/MSCs significantly inhibited the formation of liver fibrosis in rats undergoing SFSLT, while MSCs and HGF had synergistic effects in the process. The antifibrosis effect of HGF/MSCs may have contributed in modulating the activation and apoptosis of HSCs, elevating the rHGF expression level, and decreasing the TGF-beta(1) secretion of activated HSCs. These studies suggest that HGF/MSCs may be a novel therapeutic option for the treatment of liver fibrosis after SFSLT.
Yu
Yue
Y
Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Lu
Ling
L
Qian
Xiaofeng
X
Chen
Nian
N
Yao
Aihua
A
Pu
Liyong
L
Zhang
Feng
F
Li
Xiangcheng
X
Kong
Lianbao
L
Sun
Beicheng
B
Wang
Xuehao
X
D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D007797:Laminin / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008111:Liver Function Tests; D016031:Liver Transplantation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D007797:Laminin; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D006820:Hyaluronic Acid; D001973:Bromodeoxyuridine; D006909:Hydroxyproline