lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling
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Junyi Liao1,2, Xinyi Yu1,2, Xue Hu1,2, Jiaming Fan2,3, Jing Wang1,2, Zhicai Zhang2,4, Chen Zhao1,2, Zongyue Zeng2,3, Yi Shu2,3, Ruyi Zhang2,3, Shujuan Yan2,3, Yasha Li2,3, Wenwen Zhang2,5, Jing Cui2,3, Chao Ma2,6, Li Li2,7, Yichun Yu2,8, Tingting Wu2,6, Xingye Wu1,2, Jiayan Lei1,2, Jia Wang2,3, Chao Yang2,3, Ke Wu2,3, Ying Wu2,9, Jun Tang10, Bai-Cheng He2,3, Zhong-Liang Deng2,3, Hue H. Luu2, Rex C. Haydon2, Russell R. Reid2,11, Michael J. Lee2, Jennifer Moriatis Wolf2, Wei Huang1 and Tong-Chuan He2,3
1Departments of Orthopaedic Surgery, Blood Transfusion, Nephrology, and General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA
3Ministry of Education Key Laboratory of Diagnostic Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing, China
4Department of Orthopaedic Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
5Department of Laboratory Medicine and Clinical Diagnostics, The Affiliated Yantai Hospital, Binzhou Medical University, Yantai, China
6Departments of Neurosurgery, and Otolaryngology-Head & Neck Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China
7Department of Biomedical Engineering, School of Bioengineering, Chongqing University, Chongqing, China
8Department of Emergency Medicine, Beijing Hospital, Beijing, China
9Department of Immunology and Microbiology, Beijing University of Chinese Medicine, Beijing, China
10Cytate Institute for Precision Medicine & Innovation, Guangzhou Cytate Biomedical Technologies Inc., Guangzhou, China
11Department of Surgery, Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL, USA
Tong-Chuan He, email: [email protected]
Wei Huang, email: [email protected]
Keywords: mesenchymal stem cells, BMP9, osteogenic differentiation, lncRNA H19, Notch signaling
Received: March 16, 2017 Accepted: May 23, 2017 Published: June 27, 2017
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.
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