Abstract
MicroRNAs (miRNAs) emerge as important regulators of stem cell lineage commitment and bone development. MiRNA-26a (miR-26a) is one of the important miRNAs regulating osteogenic differentiation of both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs). However, miR-26a functions oppositely in osteogenic differentiation of BMSCs and ADSCs, suggesting distinct post-transcriptional regulation of tissue-specific MSC differentiation. However, the molecular basis is largely unknown. Here, we report that the function of miR-26a is largely depended on the intrinsic signaling regulation network of MSCs. Using bioinformatics and functional assay, we confirmed that miR-26a potentially targeted on GSK3β and Smad1 to regulate Wnt and BMP signaling pathway. Overall comparative analysis revealed that Wnt signaling was enhanced more potently and played a more important role than BMP signaling in osteogenic differentiation of BMSCs, whereas BMP pathway was more essential for promoting osteogenic differentiation of ADSCs. The distinct activation pattern and role of signaling pathways determined that miR-26a majorly targeted on GSK3β to activate Wnt signaling for promoting osteogenic differentiation of BMSCs, whereas it inhibited Smad1 to suppress BMP signaling for interfering with the osteogenic differentiation of ADSCs. Taken together, our study demonstrated that BMSCs and ADSCs applied different signaling pathway to facilitate their osteogenic differentiation, which determined the inverse function of miR-26a. The distinct transcriptional regulation and post-transcriptional regulation network suggested the intrinsic molecular differences between tissue-specific MSCs and the complexity in MSC research and MSC-based cell therapy.
Highlights
One recent breakthrough is that microRNAs, a class of 22–24 bp noncoding RNAs, emerge as important regulatory mechanism of mesenchymal stem cell (MSC) lineage commitment and bone development.[4,5] Several miRNAs have been identified as important regulators of osteogenesis.[6]
The expression of miR-26a was significantly increased during osteogenic differentiation of both bone marrow-derived mesenchymal stem cell (BMSC) and adipose tissue-derived mesenchymal stem cell (ADSC) (Figures 1a and b)
Consistent with the in vitro results, active β-catenin protein level in BMSCs was significantly higher than that in ADSCs, whereas pSmad[1] protein accumulation in BMSCs was lower than that in ADSCs (Figures 5h and i). These results indicated that Wnt signaling is dominantly activated during osteogenic differentiation of BMSCs, whereas bone morphogenetic protein (BMP) signaling is more active during ADSC differentiation
Summary
One recent breakthrough is that microRNAs (miRNAs), a class of 22–24 bp noncoding RNAs, emerge as important regulatory mechanism of MSC lineage commitment and bone development.[4,5] Several miRNAs have been identified as important regulators of osteogenesis.[6] Among them, miR-26a is one of the important miRNAs regulating the osteogenic differentiation of both bone marrow-derived. MSCs (BMSCs) and adipose tissue-derived MSCs (ADSCs). Expression of miR-26a is significantly increased in both BMSCs and ADSCs under osteogenic induction.[7,8,9]. Received 15.5.2015; revised 01.7.2015; accepted 02.7.2015; Edited by A Stephanou function between BMSCs and ADSCs. the molecular basis is totally unknown
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