title: Up regulation of liver-enriched transcription factors HNF4a and HNF6 and liver-specific microRNA (miR-122) by inhibition of let-7b in mesenchymal stem cells.
abstract: MicroRNAs are small non-coding RNAs that regulate key processes of the stem cells. Although, microRNAs have emerged as powerful regulators of differentiation, few studies have been focused on the post-transcriptional regulation of hepatic differentiation in mesenchymal stem cells (MSCs) by microRNAs. The aim of this study was to evaluate the specific effect of let-7 microRNAs in particular let-7b in hepatic commitment of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs). The dynamic expression profile of let-7a, b, c microRNAs and two liver-enriched transcription factors (LETFs) HNF4a and HNF6 was studied during in vitro hepatic differentiation of hAT-MSCs. Let-7b was used for transient overexpression and knockdown investigations. It was shown that the expression of LETFs is inversely correlated with those of let-7 miRNAs during differentiation progress (p < 0.05). Inhibition of let-7b caused upregulation of LETFs, an increase in the expression of miR-122 (p < 0.01) emulating the features of functional hepatocytes, and accumulation of hAT-MSCs in the G0 /G1 phase of cell cycle, triggering initiation of hepatic commitment. In conclusion, transient inhibition of let-7b activates hepatic differentiation of hAT-MSCs. The findings of this work might help optimization of in vitro hepatogenic differentiation utilizing microRNAs and hAT-MSCs that could be used for therapeutic purposes.
authors: Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
authors: Effat
authors: E
authors: Alizadeh
authors: Abolfazl
authors: A
authors: Akbarzadeh
authors: Mohamadreza Baghaban
authors: MB
authors: Eslaminejad
authors: Abolfazl
authors: A
authors: Barzegar
authors: Shahryar
authors: S
authors: Hashemzadeh
authors: Kazem
authors: K
authors: Nejati-Koshki
authors: Nosratollah
authors: N
authors: Zarghami
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D051559:Hepatocyte Nuclear Factor 6; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; C487931:mirnlet7 microRNA, human
keywords: HNF4α; HNF6; Let-7b; adipose tissue; hepatogenic differentiation; inhibition; mesenchymal stem cells; miR-122