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LIVER AND BILIARY TRACT

A role of Wnt/-catenin signals in hepatic fate specification of human umbilical cord blood-derived mesenchymal stem cells

¹Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University; ²Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University; ³Division of Regenerative Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University; and ⁴Department of Reproductive Biology and Pathology, National Research Institute for Child Health and Development, Tokyo, Japan

Submitted 30 April 2007 ; accepted in final form 7 September 2007

Human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) are expected to be an excellent source of cells for transplantation. In addition, the stem cell plasticity of human UCBMSCs, which can transdifferentiate into hepatocytes, has been reported. However, the mechanisms involved remain to be clarified. To identify the genes and/or signals that are important in specifying the hepatic fate of human UCBMSCs, we analyzed gene expression profiles during the hepatic differentiation of UCBMSCs with human telomerase reverse transcriptase, UCBMSCs immortalized by infection with a retrovirus carrying telomerase reverse transcriptase, but whose differentiation potential remains unchanged. Efficient differentiation was induced by 5-azacytidine (5-aza)/hepatocyte growth factor (HGF)/oncostatin M (OSM)/fibroblast growth factor 2 (FGF2) treatment in terms of function as well as protein expression: 2.5-fold increase in albumin, 4-fold increase in CCAAT enhancer-binding protein , 1.5-fold increase in cytochrome p450 1A1/2, and 8-fold increase in periodic acid-Schiff staining. Consequently, we found that the expression of Wnt/-catenin-related genes downregulated, and the translocation of -catenin was observed along the cell membrane and in the cytoplasm, although some -catenin was still in the nucleus. Downregulation of Wnt/-catenin signals in the cells by Fz8-small interference RNA treatment, which was analyzed with a Tcf4 promoter-luciferase assay, resulted in similar hepatic differentiation to that observed with 5-azacytidine/HGF/OSM/FGF2. In addition, the subcellular distribution of -catenin was similar to that of cells treated with 5-azacytidine/HGF/OSM/FGF2. In conclusion, the suppression of Wnt/-catenin signaling induced the hepatic differentiation of UCBMSCs, suggesting that Wnt/-catenin signals play an important role in the hepatic fate specification of human UCBMSCs.

mesenchymal stem cell; Wnt/-catenin signaling pathway; hepatic differentiation