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Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

ABSTRACT: The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14-16 weeks) and old (>1.5 years) wild-type (WT) littermates and global Opn knockout (Opn-/- ) mice for HPSC mobilization to the liver. In addition, WT and Opn-/- mice were chronically fed the Lieber-DeCarli diet for 7 weeks. Bone marrow (BM), blood, spleen, and liver were analyzed by flow cytometry for HPSC progenitors and polymorphonuclear neutrophils (PMNs). Chemokines, growth factors, and cytokines were measured in serum and liver. Prussian blue staining for iron deposits and naphthol AS-D chloroacetate esterase staining for PMNs were performed on liver sections. Hematopoietic progenitors were lower in liver and BM of young compared to old Opn-/- mice. Granulocyte colony-stimulating factor and macrophage colony-stimulating factor were increased in Opn-/- mice, suggesting potential migration of HPSCs from the BM to the liver. Furthermore, ethanol-fed Opn-/- mice showed significant hepatic PMN infiltration and hemosiderin compared to WT mice. As a result, ethanol feeding caused greater liver injury in Opn-/- compared to WT mice. Conclusion: Opn deletion promotes HPSC mobilization, PMN infiltration, and iron deposits in the liver and thereby enhances the severity of ALD. The age-associated contribution of OPN to HPSC mobilization to the liver, the prevalence of PMNs, and accumulation of hepatic iron, which potentiates oxidant stress, reveal novel signaling mechanisms that could be targeted for therapeutic benefit in patients with ALD. (Hepatology Communications 2018;2:84-98).

SUBMITTER: Magdaleno F

PROVIDER: S-EPMC5776866 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

Magdaleno Fernando F Ge Xiaodong X Fey Holger H Lu Yongke Y Gaskell Harriet H Blajszczak Chuck C CC Aloman Costica C Fiel M Isabel MI Nieto Natalia N

Hepatology communications 20171112 1

The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14-16 weeks) and old (>1.5 years) wild-type (WT) littermates and global Opn knockout (Opn-/- ) mice for HPSC mobilization to the liver. In addition, WT and Opn-/- mice were chronically fed the Lieber-DeCarli diet for 7 weeks. Bone marrow (BM), blood, s ...[more]

PMID: 29404515

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Project description:AimTo investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models.MethodsOPN pathway was evaluated in livers from patients with progressive stages of human ALD and serum from drinkers with and without liver cirrhosis. In vitro stellate LX2 cells exposed to acute alcohol and in vivo in acute alcoholic steatosis mouse models were also investigated for OPN pathway expression and function. WT and OPN(-/-) mice were administered an acute dose of alcohol and extent of liver injury was examined by histopathology and liver biochemistry after 16-24 h. The causative role of OPN was studied in OPN knockout animals and in vitro in stellate LX2 cells, utilizing siRNA, aptamer and neutralizing antibodies to block OPN and OPN pathway. OPN pathway expression and downstream functional consequences were measured for signaling by Western blotting, plasmin activation by spectrophotometric assays and cell migration by confocal imaging and quantitation.ResultsOPN expression positively correlated with disease severity in patients with progressive stages of ALD. In vivo, associated with alcoholic steatosis, a single dose of acute alcohol significantly increased hepatic OPN mRNA and protein, and a cleaved OPN form in a dose dependent manner. OPN mRNA and secreted OPN also increased in parallel with activation of LX2 stellate cells within 4 h of a single dose of alcohol. Expression of OPN receptors, αvβ3-integrin and CD44, increased in human ALD, and in vivo and in vitro with alcohol administration. This was accompanied by downstream phosphorylation of Akt and Erk, increased mRNA expression of several fibrogenesis, fibrinolysis and extracellular matrix pathway genes, plasmin activation and hepatic stellate cell (HSC) migration. Inhibition of OPN and OPN-receptor mediated signaling partially inhibited alcohol-induced HSC activation, plasmin activity and cell migration.ConclusionOPN is a key mediator of the alcohol-induced effects on hepatic stellate cell functions and liver fibrogenesis.

Project description:BackgroundOsteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis.Methodology/principal findingsOPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGF? expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F ? 2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F ? 2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury.Conclusion/significanceOPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.

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Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

Publications

Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

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