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Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells.

ABSTRACT: Reconstitution of healthy endothelial cells in vascular beds offers opportunities for mechanisms in tissue homeostasis, organ regeneration, and correction of deficient functions. Liver sinusoidal endothelial cells express unique functions, and their transplantation is relevant for disease models and for cell therapy. As molecular targets for improving transplanted cell engraftment and proliferation will be highly significant, this study determined whether ET_A/B receptor antagonism by the drug bosentan could overcome cell losses due to cell transplantation-induced cytotoxicity. Cell engraftment and proliferation assays were performed with healthy wild-type liver sinusoidal endothelial cells transplanted into the liver of dipeptidylpeptidase IV knockout mice. Transplanted cells were identified in tissues by enzyme histochemistry. Cells with prospective ET_A/B antagonism engrafted significantly better in hepatic sinusoids. Moreover, these cells underwent multiple rounds of division under liver repopulation conditions. The gains of ET_A/B antagonism resulted from benefits in cell viability and membrane integrity. Also, in bosentan-treated cells, mitochondrial homeostasis was better maintained with less oxidative stress and DNA damage after injuries. Intracellular effects of ET_A/B antagonism were transduced by conservation of ataxia telangiectasia mutated protein, which directs DNA damage response. Therefore, ET_A/B antagonism in donor cells will advance vascular reconstitution. Extensive experience with ET_A/B antagonists will facilitate translation in people.

SUBMITTER: Yadav N

PROVIDER: S-EPMC6437629 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells.

Yadav Neelam N Jaber Fadi Luc FL Sharma Yogeshwar Y Gupta Priya P Viswanathan Preeti P Gupta Sanjeev S

Human gene therapy 20181218 3

Reconstitution of healthy endothelial cells in vascular beds offers opportunities for mechanisms in tissue homeostasis, organ regeneration, and correction of deficient functions. Liver sinusoidal endothelial cells express unique functions, and their transplantation is relevant for disease models and for cell therapy. As molecular targets for improving transplanted cell engraftment and proliferation will be highly significant, this study determined whether ET<sub>A/B</sub> receptor antagonism by ...[more]

PMID: 30266073

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Project description:BackgroundBased on the gut-liver axis theory, a leaky gut can aggravate liver injury. However, clinical studies suggest that although gut mucosa damage is commonly observed in inflammatory bowel disease (IBD), it seldom leads to severe liver injury. We hypothesize that there is a hepatic barrier in the gut-liver axis, which protects the liver against gut-derived invasive factors.MethodsColitis was induced by dextran sulfate sodium (DSS) in eight different liver injury models in Sprague-Dawley rats. Liver sinusoidal endothelial cell (LSEC) injury was evaluated by a scanning and transmission electron microscope. Neutrophils were depleted by injection of anti-rat polymorphonuclear serum. Two pneumonia models were also induced to investigate the mechanism of neutrophil recruitment and activation. LSECs isolated from rat liver were used to investigate the effect on neutrophil recruitment and activation.ResultsAmong eight liver injury models, DSS colitis had no effect on liver injury in three models with normal LSECs. In the other five models with LSEC rupture, liver injury was significantly exacerbated by colitis, and increased hepatic neutrophil accumulation was observed. When neutrophils were depleted, colitis-induced liver injury was significantly attenuated. In pneumonia, liver injury, and colitis models, the level of CXCL1 correlated with the recruitment of neutrophils in different tissues, while DSS colitis and LSEC injury synergistically contributed to increased CXCL1 expression in the liver. In colitis-induced liver injury, neutrophils were activated in the liver. Injured LSECs showed both structural and functional changes, with significantly increased expression of CXCL1 and TNF-α under the stimulation of lipopolysaccharide (LPS). The combination of gut-derived LPS and LSEC-derived TNF-α led to the activation of neutrophils, characterized by enhanced production of reactive oxygen species, pro-inflammatory cytokines, and the formation of neutrophil extracellular traps.ConclusionLSECs constitute a vitally important barrier in the gut-liver axis, defending the liver against colitis-induced injury. When LSECs are damaged, they can turn into a pro-inflammatory pattern under the stimulation of LPS. LSEC injury and colitis-derived LPS synergistically contribute to the recruitment and activation of hepatic neutrophils. Neutrophils play a pivotal role as a downstream effector in colitis-induced liver injury.

Dataset Information

Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells.

Publications

Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells.

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