Signaling Regulation of Human MSC Osteogenic Differentiation: Metanalysis and Bioinformatic Analysis of MicroRNA Impact

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. With meta-analysis, the authors identified mirs significantly involved in hMSCs osteogenic differentiation. Statistical analysis revealed a significant trend of upregulation of let-7a, mir-21, mir-26a, mir-29b, mir-101, mir-143, and 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, the authors identified predictable genes-target for each mirs and analyzed signaling networks and biological process enriched by these genes. Bioinformatic assay shows that mirNAs specifically involved in hMSCs transition into osteogenic differentiation via microenvironment formation (i.e., let-7a, mir-17, mir-21, mir-29b, and mir-101), TGF-beta/BMP-SMAD-dependent pathway (i.e., let-7a, mir-17, mir-21, mir-26a, and 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 transcriptional factors are 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 sig-naling-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. The data presented here expands knowledge in the field of hMSCs' fate and osteogenesis orchestration by mirs and points to proosteogenic and antiosteogenic mirs and their potential molecular pathways.