Hepatic fibrosis is the outcome of chronic liver diseases, including cholestatic liver disease (primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), secondary biliary cirrhosis (SBC) and toxic liver injury (hepatitis B viru (HBV), hepatitis C virus (HCV), alcoholic liver disease and non-alcoholic steatohepatitis (NASH). It is characterized by extensive deposition of extracellular matrix (ECM), including collagen Type I. Activated liver resident hepatic stellate cells (aHSCs) and portal fibroblasts (aPFs) are the major source of the fibrous scar in the liver. aPFs have been implicated in liver fibrosis caused by cholestatic liver injury. However, the contribution of aPFs to cholestatic liver injury is not well characterized due to difficulties in cell purification and lack of identified aP specific markers. The goal of this study is to determine if aPFs play a critical role in cholestati liver fibrosis and identify the mechanisms of their activation. We have developed a novel flow cytometry-based method of aPF purification from the non-parenchymal fraction of Collagen-?1(I)-GFP mice and have identified putative aPF specific markers. We will use two models of cholestatic liver injury in mice: bile duct ligation (BDL) and deficiency of canalicular phospholipd flippase (Mdr2-/- mice) to characterize the contribution of aPFs to cholestatic liver fibrosis and identify novel markers critical for their activation (AIM 1). We will determine if expression of aP """"""""signature genes"""""""" identified by our preliminary study (including mesothelin, uroplakin 1?, basonuclin 1, asporin, proteoglycan 4, glipican 3) is upregulated in aPFs activated by either BDL or Mdr2-deficiency. Specifically, the role of mesothelin (Msln) in PF activation is investigated in BDL-Msln-/- and Mdr2-/-Msln-/- aPFs, and the gene expression profile of fibrogenic wt and Msln-/- aPFs is established. Next, the contribution of aPFs to ECM deposition is determined in transgenic mice, in which Smad2 signaling pathway is deleted specifically in aPFs (AIM 2). We anticipate that deletion of TGF-?1/Smad2 in aPFs attenuates fibrosis induced by BDL and Mdr2-deficiency. We will also determine if ablation of TGF- ?1/Smad2 affects expression of Msln in aPFs. Based on our preliminary data, Msln-/- aPFs exhibit a defect in activation when compared with wt aPFs isolated from BDL-mice. To determine the role of Msln in cultured PFs, responses of wt and Msln-/- aPFs to TGF-?, bile acids, IL-25 and IL-18 are examined with respect to proliferation, migration, and gene expression (AIM 3). Our findings in mice must be translated into patients. We propose to study the role of PFs in patients with cholestatic liver fibrosis by analyzing archived liver biopsies from patients with liver fibrosis of different etiologies, including PSC, PBC, SBC, HCV, ALD, and NASH for the presence of aPFs (?-SMA+Elastin+Thy1+Mesothelin+) and aHSCs (?-SMA+Desmin+GFAP+p75+) (AIM 4).
We aim to determine if a) PFs contribute speifically to the myofibroblast population in patients with cholestatic liver fibrosis;b) the number of PFs in patients with different stages of cholestatic lver fibrosis correlates with the fibrosis progression;and c) Msln can serve as a new marker of aPFs in patients with cholestatic liver fibrosis.
Hepatic fibrosis and its end stage, cirrhosis, represent an enormous health care burden worldwide. Understanding the mechanisms of myofibroblast activation is critical for the treatment of hepatic fibrosis, and will advance the field by providig new targets for the anti-fibrotic therapy. The goal of this study is to determine the contribution f portal fibroblasts (PFs) and Hepatic Stellate Cells (HSCs) to pathogenesis of liver fibrosis of different etiologies and characterize their fibrogenic properties, e.g. the ability to produce fibrus scar.
|Zhong, Zhenyu; Liang, Shuang; Sanchez-Lopez, Elsa et al. (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560:198-203|
|Kisseleva, Tatiana (2017) The origin of fibrogenic myofibroblasts in fibrotic liver. Hepatology 65:1039-1043|
|Koyama, Yukinori; Wang, Ping; Liang, Shuang et al. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 127:1254-1270|
|Patel, Niraj S; Hooker, Jonathan; Gonzalez, Monica et al. (2017) Weight Loss Decreases Magnetic Resonance Elastography Estimated Liver Stiffness in Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 15:463-464|
|Kim, In Hee; Xu, Jun; Liu, Xiao et al. (2016) Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice. Age (Dordr) 38:291-302|
|Wang, Ping; Koyama, Yukinori; Liu, Xiao et al. (2016) Promising Therapy Candidates for Liver Fibrosis. Front Physiol 7:47|
|Liang, Shuang; Kisseleva, Tatiana; Brenner, David A (2016) The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol 7:17|
|Duran, Angeles; Hernandez, Eloy D; Reina-Campos, Miguel et al. (2016) p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. Cancer Cell 30:595-609|
|Ma, Hsiao-Yen; Xu, Jun; Liu, Xiao et al. (2016) The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. Curr Pathobiol Rep 4:27-35|
|Soontornniyomkij, Virawudh; Kesby, James P; Soontornniyomkij, Benchawanna et al. (2016) Age and High-Fat Diet Effects on Glutamine Synthetase Immunoreactivity in Liver and Hippocampus and Recognition Memory in Mice. Curr Aging Sci 9:301-309|
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