Hepatic Stellate Cells Promote Hepatocyte Engraftment in Rat Liver After Prostaglandin-Endoperoxide Synthase Inhibition

Department of Surgery, Showa University Hospital and School of Medicine, Shinagawa-ku, Tokyo, Japan.
Gastroenterology (Impact Factor: 16.72). 04/2009; 136(7):2356-64. DOI: 10.1053/j.gastro.2009.03.003
Source: PubMed


Hepatic inflammation occurs immediately after cells are transplanted to the liver, but the mechanisms that underlie this process are not fully defined. We examined cyclooxygenase pathways that mediate hepatic inflammation through synthesis of prostaglandins, prostacyclins, thromboxanes, and other prostanoids following transplantation of hepatocytes.
We transplanted F344 rat hepatocytes into syngeneic dipeptidyl peptidase IV-deficient F344 rats. Changes in cyclooxygenase pathways were analyzed, and specific pathways were blocked pharmacologically; the effects on cell engraftment and native liver cells were determined.
Transplantation of hepatocytes induced hepatic expression of prostaglandin-endoperoxide synthases 1 and 2, which catalyze production of prostaglandin H2, as well as the downstream factor thromboxane synthase, which produces thromboxane A2 (a regulator of vascular and platelet responses in inflammation). Transplanted hepatocytes were in proximity with liver cells that expressed prostaglandin-endoperoxide synthases. The number of engrafted hepatocytes increased in rats given naproxen or celecoxib before transplantation but not in rats given furegrelate (an inhibitor of thromboxane synthase) or clopodigrel (an antiplatelet drug). Naproxen and celecoxib did not prevent hepatic ischemia or activation of neutrophils, Kupffer cells, or inflammatory cytokines, but they did induce hepatic stellate cells to express cytoprotective genes, vascular endothelial growth factor and hepatocyte growth factor, and matrix-type metalloproteinases and tissue inhibitor of metalloproteinase-1, which regulate hepatic remodeling.
Activation of cyclooxygenase pathways interferes with engraftment of transplanted hepatocytes in the liver. Pharmacologic blockade of prostaglandin-endoperoxide synthases stimulated hepatic stellate cells and improved cell engraftment.

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    • "In recent years, novel targets have been defined to improve engraftment of transplanted cells at these stages and several drug-based strategies have been developed in preclinical models that are potentially clinically relevant for enhancing cell engraftment in the liver (Table 3). The major concepts have concerned use of drugs to treat subjects prior to cell transplantation, such that vascular or inflammatory changes induced by cell transplantation are abolished or minimized, the endothelial barrier interposed between liver sinusoids and parenchyma is disrupted, or hepatic stellate cells are induced to release beneficial substances , e.g., VEGF [58] [59] [62] [63]. Similarly, novel concepts have been developed in rodents where donor cells may be modified prior to transplantation, e.g., by addition of extracellular matrix components for better endothelial adhesion or incubation with drugs to block endothelin (ET)-1 receptors, which otherwise may transduce deleterious intracellular signals to activate NF-jB-mediated cell death [63] [64]. "
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