Deciphering The Role And Molecular Mechanism Of DJ-1 In Liver Progenitor Cells Expansion

The liver is a vital solid organ in mammalian with robust regenerative capability.During acute and mild liver injury,the remaining uninjured liver cells could compensate the liver function by simple proliferation.While following chronic hepatic injury or once hepatocytes regeneration ability is severely impaired,liver progenitor cells（LPCs）may be evoked to mediate the liver regeneration.LPCs,which are rare in healthy audult liver,have a bi-potential to differentiate into hepatocytes or cholangiocytes.LPCs mediated liver regeneration is accompanied by fibrogenic and inflammatory response.Thus,these niches play a crucial role in LPCs activation.DJ-1 is a multifunctional protein involved in cancer development,anti-oxidative stress and lipid metablism.Recently,our previous study suggested that DJ-1 plays a critical role in initiating an inflammatory response,but its role in the liver progenitor cell 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 LPCs expansion.Part 1:The role of DJ-1 in LPC expansion was examined in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine（DDC）diet induced liver injury murine model.We found that DJ-1 expression was positively correlated with LPCs response in mice with DDC exposure.DJ-1 deficiency restrains the LPCs expansion.Part 2:Using an ex vivo and in vitro cell culture model,we found that neither DJ-1 knock-out（KO）nor knock-down（KD）has no direct effect on LPC proliferation.In DDC induced mice model,reduced activation of HSCs and collagen deposition were observed in DJ-1 KO mice.Furthermore,infiltrated CD11b⁺Gr-1^lowow 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.Recombinant CCL2 injection restores the marophage infiltration and LPCs activation.Additonally,we also determined the ability of hepatic stellate cells（HSCs）in recruiting macrophages in DJ-1 KO mice.Bone marrow transplantation was conducted to identify whether DJ-1 directly modulates the recruitment or activity of immune cells.These results strongly indicate that the liver resident cells but not the immune cells mainly contribute to the impaired LPCs-associated inflammatory niche in DJ-1 KO mice in the DDC model.Part 3:The correlation of DJ-1 expression with LPC markers was examined in the liver of patients with hepatitis B（HBV）or hepatitis C virus infection（HCV）,primary biliary cirrhosis（PBC）,primary sclerosing cholangitis（PSC）,nonalcoholic fatty liver disease（NAFLD）,cirrhosis or hepatocellular carcinoma（HCC）respectively.We found that the expression levels of DJ-1 were upregulated in the liver of HBV,HCV,PBC and PSC patients and DJ-1 is positively correlated with liver progenitor cells response in chronic liver injury.In conclusion,DJ-1 deficiency negatively regulates LPCs proliferation by impairing the formation of LPC-associated fibrosis and inflammatory niches.Furthermore,DJ-1 positively correlates with LPCs expansion during chronic liver disease,which suggests the clinical significance of DJ-1 in LPCs mediated regeneration.