MiR-21 Regulates Adipogenic Differentiation through the Modulation of TGF-β Signaling in Mesenchymal Stem Cells Derived from Human Adipose Tissue

Abstract

A better understanding of the molecular mechanisms that govern human adipose tissue-derived mesenchymal stem cells (hASCs) differentiation could improve hASCs-based cell therapy and provide new insights into a number of diseases, including obesity. In this study, we examined the roles of microRNA-21 (miR-21) in adipogenic differentiation of hASCs. We found that miR-21 expression was transiently increased after induction of adipogenic differentiation, peaked at 3 days, and returned to the baseline level 8 days. Lentiviral overexpression of miR-21 enhanced adipogenic differentiation. Overexpression of miR-21 decreased both protein and mRNA levels of TGFBR2. The expression of TGFBR2 was decreased during adipogenic differentiation of hASCs in concordance with an increase in the level of miR-21. In contrast, inhibiting miR-21 with 2 0 -O-methylantisense microRNA increased TGFBR2 protein levels in hASCs, accompanied by decreased adipogenic differentiation. The activity of a luciferase construct containing the miR-21 target site from the TGFBR2 3 0 UTR was lower in LV-miR21-infected hASCs than in LV-miLacZ infected cells. TGF-b-induced inhibition of adipogenic differentiation was significantly decreased in miR-21 overexpressing cells compared with control lentivirus-transduced cells. RNA interference-mediated downregulation of SMAD3, but not of SMAD2, increased adipogenic differentiation. Overexpression and inhibition of miR-21 altered SMAD3 phosphorylation without affecting total levels of SMAD3 protein. Our data are the first to demonstrate that the role of miR-21 in the adipogenic differentiation of hASCs is mediated through the modulation of TGF-b signaling. This study improves our knowledge of the molecular mechanisms governing hASCs differentiation, which may underlie the development of obesity or other metabolic diseases.

MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

“…A total of 15 miRNAs were detected to exhibit significantly differential expression in primary tumors compared to their nontumor controls by paired significance analysis of microarray (SAM) ( Figure 1A). The expression pattern of four miRNAs (miR-21, miR-25, miR-106a and miR106b) was consistent with the previous profiling study, which was confirmed by other independent reports [12,15,[17][18][19][20]. Among them, miR-375 was shown to be the most significantly downregulated miRNA in stomach tumors.…”

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

“…The TGF-beta signaling pathway is also closely related with lipometabolism. Kim et al suggested that miR-21 targeted the gene transforming growth factor beta receptor 2 (TGFBR2) to regulate adipogenic differentiation in human stem cells [36]. Moreover, we noticed that PPAR signaling pathway is important in fatty acid metabolism, sterol metabolism and adipogenic differentiation.…”

“…Previous studies have shown that some differentially and abundantly expressed miRNAs (down-regulated miRNAs: ssc-let-7i, ssc-miR-21, ssc-miR-27b-3p and up-regulated miRNAs: ssc-miR-1, ssc-miR-133a-3p, ssc-miR-486) were responsible for regulating adipogenic differentiation [36][37][38][41][42][43]. ssc-miR-1 and ssc-miR133a were found extensively in skeletal muscle tissues while ssc-miR-21, ssc-miR-27b-3p, and the Let-7 family play important roles in adipomuscle and myocardial tissue.…”

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

“…Reduced TβRII protein could result from reduced synthesis and/or increased degradation. Interestingly, we found that miR‐21, which has been shown to inhibit TβRII protein synthesis (Kim et al ., 2009; Yu et al ., 2012), is significantly induced by reduced fibroblast size/mechanical force. These data suggest a potential mechanism in which miR‐21 functions as a mechanosensitive microRNA to mediate down‐regulation of TβRII expression.…”