Let-7f microRNA negatively regulates hepatic differentiation of human adipose tissue-derived stem cells
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ORIGINAL PAPER
Let-7f microRNA negatively regulates hepatic differentiation of human adipose tissue-derived stem cells Nahid Davoodian & Abbas S. Lotfi & Masoud Soleimani & Seyed Javad Mola & Sare Arjmand
Received: 31 March 2014 / Accepted: 8 July 2014 / Published online: 31 July 2014 # University of Navarra 2014
Abstract MicroRNAs (miRNAs) are noncoding RNAs involved in the regulation of the diverse biological processes such as metabolism, proliferation, and cell cycle, in addition to regulation of differentiation. So far, some miRNAs have been recognized to have important role in regulating hepatic functions. Statistically, let-7f has been revealed as a negative regulator of hepatic differentiation. In the present study, we investigated the effect of let-7f on hepatic differentiation of human adipose tissue-derived stem cells (hADSCs). hADSCs were transduced with recombinant lentivirus containing human inhibitor let-7 f. The expression of hepatocyte nuclear factors alpha (HNF4a), albumin (ALB), alpha fetoprotein (AFP), cytokeratin 18 (CK18), and cytokeratin 19 (CK19) was evaluated using quantitative real-time PCR (qRT-PCR). Immunocytochemistry was used to investigate the expression levels of the hepatocyte markers including ALB, AFP, and HNF4a, and biochemical analysis was implemented for hepatic N. Davoodian : A. S. Lotfi (*) : S. Arjmand Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran e-mail: [email protected] M. Soleimani Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran S. J. Mola Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
function, glycogen deposition, and urea secretion. qRT-PCR showed significant upregulation in HNF4a, ALB, AFP, CK18, and CK19 expression in cells transduced with let-7f inhibitor lentiviruses. Moreover, positive staining was detected for ALB, AFP, and HNF4a using immunocytochemistry. Urea production and glycogen deposits were also found in the treated cells, the two specific features of the hepatic cells. Therefore, let7f silencing led to the increased expression of the hepatocyte-specific factors and the accelerated hADSCs hepatic differentiation. Summing all these finding together, our present report has provided evidences that inhibition of let-7f would facilitate induction of hADSCs into hepatocyte-like cells and possibly in regenerative therapy of the liver disease in a wider spectrum. Keywords MicroRNAs . Let-7f microRNA . Adipose tissue-derived stem cells . HNF4a . Hepatic differentiation
Introduction Stem cell therapy is among the exceptional candidates that have been suggested for liver disorders [29]. Many types of stem cells have already been used for generation of hepatocyte-like cells in regenerative medicine. Some studies have indicated mesenchymal stem cells (MSCs) as a preferred cell source. MSCs are a group of multipotent cells characterized by high self-renewal potential and differentiation [22]. They can be i
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