My research focuses on liver diseases. I got my Ph.D. degree in virology and immune response at Institut Pasteur of Shanghai, Chinese Academy of Sciences. The two main projects during my Ph.D. program are: 1) explore the relationship between the immune response in Hepatitis C virus infection and Interferon treatment; and 2) investigate the function of ECM1 in liver fibrosis. As a postdoc in Stanford, I will try to integrate basic and translational liver research and focus on: 1) investigate molecular functions of liver immune cells in liver disease; 2) explore key factors determining the change of liver microenvironment that cause liver diseases; 3) use new techniques, such as next-generation sequencing, RNAseq or signal cell sequencing, to explore key factors affecting liver disease and treatment in patients.
Bachelor of Science, Nanjing Agricultural College (2011)
Doctor of Philosophy, Chinese Academy Of Sciences (2018)
ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation.
Proceedings of the National Academy of Sciences of the United States of America
Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.
View details for DOI 10.1073/pnas.1912774117
View details for PubMedID 31980528
Non-phagocytic Activation of NOX2 is Implicated in Progressive Non-alcoholic Steatohepatitis During Aging.
Hepatology (Baltimore, Md.)
Older patients with obesity/type II DM frequently present with advanced non-alcoholic steatohepatitis (NASH). Whether this is due to specific molecular pathways that accelerate fibrosis during aging, is unknown. Activation of the Src homology 2 domain containing collagen-related (Shc) proteins and redox stress have been recognized in aging, however their link to NASH has not been explored. Shc expression increased in livers of older patients with NASH, as assessed by RTqPCR or western blots. Fibrosis, Shc expression, markers of senescence and NADPH oxidases (NOXs) were studied in young/old mice on fast food diet (FFD). To inhibit Shc in old mice LV-shShc vs. control-LV were used during FFD. For hepatocyte-specific effects, fl/fl Shc mice on FFD were injected with AAV8-TBG-Cre vs. control. Fibrosis was accelerated in older mice on FFD, and Shc inhibition by LV in older mice, or hepatocyte-specific deletion resulted in significantly improved inflammation, reduction in senescence markers in older mice, lipid peroxidation and fibrosis. To study NOX2 activation, the interaction of p47phox (NOX2 regulatory subunit) and p52Shc was evaluated by proximity ligation, and co-IPs. Palmitate induced p52Shc binding to p47phox activating the NOX2 complex, more so at older age. Kinetics of binding were assessed in SH2 or PTB deletion mutants by biolayer interferometry, revealing the role of SH2 and the PTB domains. Lastly, an in silico model of p52Shc/p47phox interaction using RosettaDock was generated. Conclusion Accelerated fibrosis in the aged is modulated by p52Shc/NOX2. We show a novel pathway for direct activation of the phagocytic NOX2 in hepatocytes by p52Shc binding and activating the p47phox subunit that results in redox stress, and accelerated fibrosis in the aged.
View details for DOI 10.1002/hep.31118
View details for PubMedID 31950520
ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice.
2019; 157 (5): 1352–67.e13
Activation of TGFB (transforming growth factor β) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers.We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Δhep). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization.ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Δhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice.ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.
View details for DOI 10.1053/j.gastro.2019.07.036
View details for PubMedID 31362006
Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production.
Proceedings of the National Academy of Sciences of the United States of America
2018; 115 (34): 8621–26
T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.
View details for DOI 10.1073/pnas.1801196115
View details for PubMedID 30087185
View details for PubMedCentralID PMC6112729
IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18.
The Journal of general virology
2016; 97 (9): 2210–20
The recently discovered interferon lambda 4 (IFN-λ4) is a new member of the human type III interferons which could induce a strong antiviral effect through the JAK-STAT cascade. However, hepatitis C virus (HCV) patients who are capable of expressing IFN-λ4 usually have poor response to IFN-α treatment, and the mechanism behind this paradox remains unknown. Here, we reported that IFN-λ4 desensitized IFN-α-stimulated JAK-STAT signalling. Microarray analysis revealed that IFN-λ4 could induce ubiquitin specific peptidase 18 (USP18), a known inhibitor of the type I IFN signalling pathway, in a more sustained pattern compared with type I interferon induction. Moreover, only HCV genotype 1b but not 2a replicon cells pretreated with IFN-λ4 had an attenuated response to type I IFN treatment, which might be due to the different level of USP18 expression. Consistently, knockdown of USP18 in HCV genotype 1b-containing replicon cells reversed the resistance induced by IFN-λ4 and promoted viral clearance. Finally, IFN-λ4 is also strongly associated with the poor response to IFN-α in a Chinese HCV genotype 1b cohort. In conclusion, these data indicate that IFN-λ4 attenuates the response of HCV genotype 1b to IFN-α therapy and inhibits the JAK-STAT signalling pathway by inducing USP18 expression.
View details for DOI 10.1099/jgv.0.000522
View details for PubMedID 27302182