Depolarized Hepatocytes Express the Stem/Progenitor Cell Marker Neighbor of Punc E11 After Bile Duct Ligation in Mice

There is a medical need of biomarkers for disease stratification in cholestatic liver diseases that come along with changes in hepatocyte polarity. Neighbor of Punc E11 (Nope) is an oncofetal marker that is lost after final differentiation and polarization of hepatocytes. We analyzed the expression pattern of Nope and connexin (Cx) 26 as markers of hepatocyte polarization during murine liver development as well as in adult liver with or without bile duct ligation (BDL) by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting (WB), and immunohistochemistry. Nope is highly expressed in fetal and postnatal liver but barely detectable thereafter. Cx26, however, is much higher expressed in adult than in fetal liver. Postnatally, Nope is directed to the sinusoidal membrane of early hepatocytes while Cx26 remains distributed over the whole membrane indicating limited polarization. In the adult liver, only Cx26 is detectable and restricted to the bile canalicular domain indicating fully polarized hepatocytes. After BDL, Nope is again >300-fold upregulated while Cx26 is reduced rapidly. By immunohistochemistry, Nope identifies a subset of hepatocytes with randomly distributed Cx26. In summary, Nope identifies depolarized adult hepatocytes after cholestatic liver injury resembling early postnatal hepatocytes. Therefore, Nope might be a valuable histochemical biomarker allowing stage-specific stratifications in cholestatic liver diseases.

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Human Chorionic Plate-Derived Mesenchymal Stem Cells Restore Hepatic Lipid Metabolism in a Rat Model of Bile Duct Ligation

Stem Cells International ◽

10.1155/2017/5180579 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Yun Bin Lee ◽

Jong Ho Choi ◽

Eun Nam Kim ◽

Jin Seok ◽

Hyun-Jung Lee ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Lipid Metabolism ◽

Bile Duct ◽

Rat Model ◽

Liver Diseases ◽

Bile Duct Ligation ◽

Expression Levels ◽

Duct Ligation ◽

Chorionic Plate

In cholestatic liver diseases, impaired bile excretion disrupts lipid homeostasis. We investigated changes of lipid metabolism, including mitochondrial β-oxidation, in a rat model of bile duct ligation (BDL) in which chorionic plate-derived mesenchymal stem cells (CP-MSCs) were transplanted. Serum cholesterol level, which was elevated after BDL, was significantly decreased following CP-MSC transplantation. The expression levels of genes involved in intracellular lipid uptake, including long-chain fatty acyl-CoA synthetases and fatty acid transport proteins, were decreased in rats after BDL; however, they were not significantly changed by subsequent CP-MSC transplantation. Carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme in mitochondrial β-oxidation, was upregulated after BDL and then was downregulated after CP-MSC transplantation. CPT1A expression was changed via microRNA-33—a posttranscriptional regulator of CPT1A—in a peroxisome proliferator-activated receptor α-independent manner. Cellular adenosine triphosphate production—an indicator of mitochondrial function—was reduced after BDL and was restored by CP-MSC transplantation. Expression levels of heme oxygenases also were significantly affected following BDL and CP-MSC transplantation. Lipid metabolism is altered in response to chronic cholestatic liver injury and can be restored by CP-MSC transplantation. Our study findings support the therapeutic potential of CP-MSCs in cholestatic liver diseases and help in understanding the fundamental mechanisms by which CP-MSCs affect energy metabolism.

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