DJ-1 deficiency attenuates expansion of liver progenitor cells through modulating the inflammatory and fibrogenic niches.
Our previous study suggested that DJ-1 has a critical role in initiating an inflammatory response, but its role in the liver progenitor cell (LPC) expansion, a process highly dependent on the inflammatory niche, remains elusive. The objective of this study is to determine the role of DJ-1 in LPC expansion. The correlation of DJ-1 expression with LPC markers was examined in the liver of patients with hepatitis B or hepatitis C virus (HBV and HCV, respectively) infection, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic fatty liver disease (NAFLD), cirrhosis or hepatocellular carcinoma (HCC), respectively. The role of DJ-1 in LPC expansion and the formation of LPC-associated fibrosis and inflammation was examined in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced liver injury murine model. We also determined the ability of hepatic stellate cells (HSCs) in recruiting macrophages in DJ-1 knockout (KO) mice. The expression levels of DJ-1 were upregulated in the liver of HBV, HCV, PBC and PSC patients and DDC-fed mice. Additionally, DJ-1 expression was positively correlated with LPC proliferation in patients with liver injury and mice with DDC exposure. DJ-1 has no direct effect on LPC proliferation. Reduced activation of HSCs and collagen deposition were observed in DJ-1 KO mice. Furthermore, infiltrated CD11b(+)Gr-1(low) macrophages and pro-inflammatory factors (IL-6, TNF-α) were attenuated in DJ-1 KO mice. Mechanistically, we found that HSCs isolated from DJ-1 KO mice had decreased secretion of macrophage-mobilizing chemokines, such as CCL2 and CX3CL1, resulting in impaired macrophage infiltration. DJ-1 positively correlates with LPC expansion during liver injury. DJ-1 deficiency negatively regulates LPC proliferation by impairing the formation of LPC-associated fibrosis and inflammatory niches.
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
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L
Chen
Department of General Surgery, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
M
M
Luo
Department of Liver Diseases, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China.
X
X
Sun
Department of GI Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, Shanghai, China.
J
J
Qin
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
C
C
Yu
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Y
Y
Wen
School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Q
Q
Zhang
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J
J
Gu
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Q
Q
Xia
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
X
X
Kong
D000818:Animals; D031204:Caloric Restriction; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000494:pharmacology; D004032:Diet; D015972:Gene Expression Regulation, Neoplastic; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071617:Protein Deglycase DJ-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics
C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D018932:Chemokine CCL2; D011725:Pyridines; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1