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Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD, which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC.

Mesenchymal stem cells (MSCs) are an attractive cell source for cell therapy. Based on our hypothesis that suppression of Wnt/β-catenin signal enhances hepatic differentiation of human MSCs, we developed human mesenchymal stem cell-engineered hepatic cell sheets by a small molecule compound. Screening of 10 small molecule compounds was performed by WST assay, TCF reporter assay, and albumin mRNA expression. Consequently, hexachlorophene suppressed TCF reporter activity in time- and concentration-dependent manner. Hexachlorophene rapidly induced hepatic differentiation of human MSCs judging from expression of liver-specific genes and proteins, PAS staining, and urea production. The effect of orthotopic transplantation of human mesenchymal stem cell-engineered hepatic cell sheets against acute liver injury was examined in one-layered to three-layered cell sheets system. Transplantation of human mesenchymal stem cell-engineered hepatic cell sheets enhanced liver regeneration and suppressed liver injury. The survival rates of the mice were significantly improved. High expression of complement C3 and its downstream signals including C5a, NF-κB, and IL-6/STAT-3 pathway was observed in hepatic cell sheets-grafted tissues. Expression of phosphorylated EGFR and thioredoxin is enhanced, resulting in reduction of oxidative stress. These findings suggest that orthotopic transplantation of hepatic cell sheets manufactured from MSCs accelerates liver regeneration through complement C3, EGFR and thioredoxin.

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We previously reported that impaired retinoid signaling causes hepatocellular carcinoma (HCC) through oxidative stress. However, the interaction between oxidative stress and retinoid signaling has not been fully understood. To address this issue, the effects of hydrogen peroxide on the transcriptional activity of RAR ⁄ RXR heterodimers, RARa and RXRa proteins and intracellular signaling pathways were examined. The transcriptional activity of RAR ⁄ RXR examined by the DR5-tk-Luc reporter assay was significantly suppressed. The RARa protein level began to decrease at 6 h after treatment and declined thereafter. However, RARa mRNA were not changed. Activation of extracellular regulated kinases (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt was observed after treatment of hydrogen peroxide. SP600125, an inhibitor of JNK, reversed the RARa protein level reduced by hydrogen peroxide. Anisomycin, an activator of JNK, reduced RARa protein. Transfection of wild-type JNK-constitutive actively expressing plasmid, but not kinase-negative JNK-expressing plasmid caused reduction of RARa protein. Proteasomal degradation of RARa was observed after anisomycin treatment; however, the mutant RARa, of which phosphorylation sites are replaced with alanines, was not degradated. In hepatitis C virus (HCV)-related human liver tissues, phospho-JNK and RARa reciprocally expressed with the progression of liver disease. Finally, the staining of 8-OHdG and thioredoxin was increased with the disease progression. These data indicate that JNK activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of RARa, suggesting that a vicious cycle between aberrant retinoid signaling and oxidative stress accelerates hepatocarcinogenesis. (Cancer Sci 2011; 102: 934-941) R etinoids, most notably retinoic acids (RA), exert a wide variety of profound effects on vertebrate development, differentiation and homeostasis.(1-4) Recently, retinoids are regarded as useful pharmacological tools in revealing important pathways targeted in cancer therapy and chemoprevention. (5) In the liver, decreased vitamin A storage in hepatic stellate cells (HSC) in pathological conditions such as liver cirrhosis (LC) has been observed, (6) implying a relationship between the loss of retinoid signaling and the development of hepatocellular carcinoma (HCC). Indeed, the decreases in hepatic retinol and retinyl esters were observed in patients with LC, which is a predisposition to the development of HCC.(7) A large-scale cohort study of hepatitis B virus surface antigen (HBsAg)-positive subjects has revealed that the odds ratio of HCC in the subjects with low serum retinol is about sevenfold higher than those with high serum retinol.(8) Taken together, we hypothesize that HSC activation would result in a significant alteration in retinoid metabolism, leading to the development of HCC. We have recently demonstrated that the impaired retinoid signaling in the liver causes steatohepatitis and HCC through oxidative stress induced by aberrant me...