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Oncotarget. 2017 Jun 27;8(32):53581-53601. doi: 10.18632/oncotarget.18655. eCollection 2017 Aug 8.

lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling.

Liao J1,2, Yu X1,2, Hu X1,2, Fan J2,3, Wang J1,2, Zhang Z2,4, Zhao C1,2, Zeng Z2,3, Shu Y2,3, Zhang R2,3, Yan S2,3, Li Y2,3, Zhang W2,5, Cui J2,3, Ma C2,6, Li L2,7, Yu Y2,8, Wu T2,6, Wu X1,2, Lei J1,2, Wang J2,3, Yang C2,3, Wu K2,3, Wu Y2,9, Tang J10, He BC2,3, Deng ZL2,3, Luu HH2, Haydon RC2, Reid RR2,11, Lee MJ2, Wolf JM2, Huang W1, He TC2,3.

Author information

1
Departments of Orthopaedic Surgery, Blood Transfusion, Nephrology, and General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
2
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
3
Ministry of Education Key Laboratory of Diagnostic Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
4
Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
5
Department of Laboratory Medicine and Clinical Diagnostics, The Affiliated Yantai Hospital, Binzhou Medical University, Yantai, China.
6
Departments of Neurosurgery, and Otolaryngology-Head & Neck Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China.
7
Department of Biomedical Engineering, School of Bioengineering, Chongqing University, Chongqing, China.
8
Department of Emergency Medicine, Beijing Hospital, Beijing, China.
9
Department of Immunology and Microbiology, Beijing University of Chinese Medicine, Beijing, China.
10
Cytate Institute for Precision Medicine & Innovation, Guangzhou Cytate Biomedical Technologies Inc., Guangzhou, China.
11
Department of Surgery, Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL, USA.

Abstract

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can undergo self-renewal and differentiate into multiple lineages. Osteogenic differentiation from MSCs is a well-orchestrated process and regulated by multiple signaling pathways. We previously demonstrated that BMP9 is one of the most potent osteogenic factors. However, molecular mechanism through which BMP9 governs osteoblastic differentiation remains to be fully understood. Increasing evidence indicates noncoding RNAs (ncRNAs) may play important regulatory roles in many physiological and/or pathologic processes. In this study, we investigate the role of lncRNA H19 in BMP9-regulated osteogenic differentiation of MSCs. We demonstrated that H19 was sharply upregulated at the early stage of BMP9 stimulation of MSCs, followed by a rapid decease and gradual return to basal level. This process was correlated with BMP9-induced expression of osteogenic markers. Interestingly, either constitutive H19 expression or silencing H19 expression in MSCs significantly impaired BMP9-induced osteogenic differentiation in vitro and in vivo, which was effectively rescued by the activation of Notch signaling. Either constitutive H19 expression or silencing H19 expression led to the increased expression of a group of miRNAs that are predicted to target Notch ligands and receptors. Thus, these results indicate that lncRNA H19 functions as an important mediator of BMP9 signaling by modulating Notch signaling-targeting miRNAs. Our findings suggest that the well-coordinated biphasic expression of lncRNA H19 may be essential in BMP9-induced osteogenic differentiation of MSCs, and that dysregulated H19 expression may impair normal osteogenesis, leading to pathogenic processes, such as bone tumor development.

KEYWORDS:

BMP9; Notch signaling; lncRNA H19; mesenchymal stem cells; osteogenic differentiation

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