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

Abstract

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 α, 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/β-catenin-related genes downregulated, and the translocation of β-catenin was observed along the cell membrane and in the cytoplasm, although some β-catenin was still in the nucleus. Downregulation of Wnt/β-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 β-catenin was similar to that of cells treated with 5-azacytidine/HGF/OSM/FGF2. In conclusion, the suppression of Wnt/β-catenin signaling induced the hepatic differentiation of UCBMSCs, suggesting that Wnt/β-catenin signals play an important role in the hepatic fate specification of human UCBMSCs.

Activation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration

“…34 Our results are consistent with other studies suggesting that down-regulation of Wnt/b-catenin signaling is necessary for stem cell differentiation. 10,11 The presence of Wnt ligands can enhance the binding of b-catenin to androgen receptor (AR) and promote AR-mediated transcription. 35 Others suggested that IL-6 might modulate the AR nuclear transactivation via STAT3, MAPK, or other signaling cascades.…”

“…Previous studies have suggested that suppression of the Wnt/b-catenin signaling pathway promotes hepatic differentiation of MSCs derived from bone marrow or umbilical cord blood. 10,11 In embryonic development, Wnt-5a represents the major suppression modulator of Wnt/b-catenin signaling. Overexpression of Wnt-5a promotes GSK-3b-independent b-catenin degradation, suggesting an oncosuppression effect.…”

Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis

“…Therefore, many studies have examined the mechanisms underlying the differentiation ability of MSCs. Several recent studies (Yoshida et al, 2007;Ishii et al, 2008;Liu et al, 2015) have demonstrated that Wnt/β-catenin signaling plays an important role in regulating the hepatic differentiation of human MSCs. Upon Wnt signaling activation, β-catenin will translocate into the nucleus and coactivate downstream transcription factors to regulate the differentiation of MSCs.…”

Dental Stem Cell Differentiation Toward Endodermal Cell Lineages: Approaches to Control Hepatocytes and Beta Cell Transformation

“…During the hepatoblast formation by both hepatic liver cells and biliary epithelial cells [ 14 ], Wnt/β-catenin is known to promote cell proliferation and differentiation along with the formation of progenitor hepatocytes [ 101 ]. The activation of this signalling pathway allows the conversion of non-hepatic endodermal cells to a hepatoblast condition.…”