Bioinformatic Analysis of MicroRNAs and Signaling Networks that Orchestrates the hMSC Osteogenic Differentiation

Background: The drive to understand how microRNAs regulate the hMSCs fate and their osteogenic differentiation has inspired stem cells biology and regenerative biology field development. Numerous experimental data shows crucial involvement of miRs in skeletal development in embryos, osteogenic differentiation, and maturation. However, molecular mechanisms of miRs action, in other words their target signaling pathways and transcriptional factors that specific drives osteogenic differentiation is far from being understood. Results With meta-analysis we identified miRs significantly involved in hMSCs osteogenic differentiation. Statistical analysis revealed significant trend of upregulation of let-7a, mir-21, mir-26a, mir-29b, mir-101, mir-143, mir-218 during hMSCs differentiation into osteoblast. And the opposite trend was shown for mir-17, mir-31, mir-138 and mir-222: their content was significantly lower during osteogenic differentiation. Using bioinformatics approaches we identified predictable genes-target for each miRs, analyzed signaling networks and biological process enriched by these genes. Conclusions Our date shows that miRNAs specifically involved in hMSC transition into osteogenic differentiation via microenvironment formation (i.e. let-7a, mir-17, mir-21, mir-29b and mir-101), TGF-β/BMP–SMAD dependent pathway (i.e. let-7a, mir-17, mir-21, mir-26a mir-101) and MAPK signaling pathway (i.e. let-7a, mir-21, mir-26a, mir-29b, mir-143 and mir17). Yap-dependent expression of osteogenic TF modulated by let-7a, mir-31mir-101, mir-138 and mir-222. We predicted that mir-17, mir-26a, mir-29b, mir-101, mir-138 and mir-222 are specifically involved in canonical Wnt signaling dependent osteogenesis as well as in osteoblast maturation together with let-7a, mir-29b and mir-218 which modulate AMPK signaling. Additionally, identified mir-101 is likely involved into osteoblast homeostasis via Hedgehog signaling. Our data expands knowledge in the field of hMSCs fate and osteogenesis orchestration by miRs, points to pro-osteogenic and anti-osteogenic miRs and their potential molecular pathways.