title: MiR-26a functions oppositely in osteogenic differentiation of BMSCs and ADSCs depending on distinct activation and roles of Wnt and BMP signaling pathway.
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.
authors.affiliation: 1] Department of Orthodontics, Stomatology Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710004, China [2] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [3] Institute of Neurobiology, Environment and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China.
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.affiliation: 1] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [2] Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Xi'an, Shaanxi 710032, China [3] State Key Laboratory of Military Stomatology, Department of Oral Histology and pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: L
authors.initials: L
authors.lastname: Liao
authors.affiliation: 1] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [2] Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Xi'an, Shaanxi 710032, China [3] State Key Laboratory of Military Stomatology, Department of Oral Histology and pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shuai
authors.affiliation: 1] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [2] Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Xi'an, Shaanxi 710032, China [3] State Key Laboratory of Military Stomatology, Department of Oral Histology and pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: H
authors.initials: H
authors.lastname: Jing
authors.affiliation: 1] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [2] Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Xi'an, Shaanxi 710032, China [3] State Key Laboratory of Military Stomatology, Department of Oral Histology and pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Orthodontics, Stomatology Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710004, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Institute of Neurobiology, Environment and Genes Related to Diseases, Key Laboratory of Education Ministry, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China [2] Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Xi'an, Shaanxi 710032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D010012:Osteogenesis / Q000235:genetics; D061251:Primary Cell Culture; D011485:Protein Binding; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C543693:Mirn26 microRNA, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D052004:Bone Morphogenetic Protein Receptors