β-catenin-coordinated lncRNA MALAT1 up-regulation of ZEB-1 could enhance the telomerase activity in HGF-mediated differentiation of bone marrow mesenchymal stem cells into hepatocytes

• Published in: Pathology, research and practice Vol. 215; no. 3; pp. 546 - 554
• Main Authors: Tan, Yan-Fang, Tang, Lian, OuYang, Wen-Xian, Jiang, Tao, Zhang, Hui, Li, Shuang-Jie
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.03.2019
• Subjects: BM-MSCs; MALAT1; miRNA-217-3p; TERT; ZEB1; β-Catenin; β-Catenin; miRNA-217-3p; MALAT1; ZEB1; TERT; BM-MSCs
• ISSN: 0344-0338; 1618-0631
• DOI: 10.1016/j.prp.2019.01.002

To investigate role of β-catenin and lncRNA MALAT1/miR-217 axis to converge into the regulation of ZEB-1 in hepatocyte growth factor (HGF)-induced hepatocytes differentiated from bone marrow mesenchymal stem cells (BM-MSCs). BM-MSCs were isolated and HGF was used to induce the differentiation of BM-MSCs into hepatocytes. HSC-T6 cells, BRL-3 A cells and differentiated BM-MSCs were treated by lipopolysaccharide(LPS). shRNAs were used to silence β-catenin and recombinant plasmids were used to over-express ZEB1. Measurement of cell viability was conducted using MTT assay and Hoechst 33342 staining. RNA immunoprecipitation (RIP) assay was used to determine binding of miR-217-3p and MALAT1. BM-MSCs successfully differentiated into hepatocytes by HGF treatment. Expression of β-catenin, ZEB-1 and TERT was up-regulated to a higher level in hepatocytes differentiated from BM-MSCs than HSC-T6 cells and BRL-3 A cells after LPS stimulation. When β-catenin was knocked down in all cell lines, expression of β-catenin, ZEB-1 and TERT was significantly decreased as well as telomerase activity. While when ZEB1 was over-expressed, expression of TERT and telomerase activity was all significantly up-regulated. In hepatocytes differentiated from BM-MSCs, miR-217 was down-regulated and lncRNA MALAT1 was up-regulated. RIP analysis showed MALAT1 was physically associated with miR-217 and might function in the regulation of ZEB-1, further enhancing the expression of TERT so as to augment telomerase activity. We successfully used HGF to mediate differentiation of BM-MSCs into hepatocytes, and found that β-catenin-coordinated MALAT1/miR-217 axis could up-regulate expression of ZEB-1 and further enhanced the telomerase activity through regulation of TERT in BM-MSCs differentiating into hepatocytes.