Adipocyte differentiation of human bone marrow-derived stromal cells is modulated by microRNA-155, microRNA-221, and microRNA-222.

Human mesenchymal stromal cells (hMSCs) are capable of limited self-renewal and multilineage differentiation in vitro. Several studies have demonstrated that microRNAs (miRNAs, miRs), post-transcriptional modifiers of mRNA stability and protein translation, play crucial roles in the regulation of these complex processes. To gain knowledge regarding the role of miRNAs in human adipocyte differentiation, we examined the miRNA expression profile of the immortalized human bone marrow-derived stromal cell line hMSC-Tert20. Such a model system has the advantage of a reproducible and consistent phenotype while maintaining important properties of the primary donor cells, including the potential to differentiate to adipocytes, osteoblasts, and chondrocytes. We identified 12 miRNAs that were differentially expressed during adipogenesis, of which several have been previously shown to play important roles in adipocyte biology. Among these, the expression of miRNA-155, miRNA-221, and miRNA-222 decreased during the adipogenic program of both immortalized and primary hMSCs, suggesting that they act as negative regulators of differentiation. Interestingly, ectopic expression of the miRNAs significantly inhibited adipogenesis and repressed induction of the master regulators PPARγ and CCAAT/enhancer-binding protein alpha. Our study provides the first experimental evidence that miRNA-155, miRNA-221, and miRNA-222 have an important function in human adipocyte differentiation, and that their downregulation is necessary to relieve the repression of genes crucial for this process.