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

Junyi Liao | Xinyi Yu | Xue Hu | Jiaming Fan | Jing Wang | Zhicai Zhang | Chen Zhao | Zongyue Zeng | Yi Shu | Ruyi Zhang | Shujuan Yan | Yasha Li | Wenwen Zhang | Jing Cui | Chao Ma | Li Li | Yichun Yu | Tingting Wu | Xingye Wu | Jiayan Lei | Jia Wang | Chao Yang | Ke Wu | Ying Wu | Jun Tang | Bai-Cheng He | Zhong-Liang Deng | Hue H Luu | Rex C Haydon | Russell R Reid | Michael J Lee | Jennifer Moriatis Wolf | Wei Huang | Tong-Chuan He
Oncotarget | 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.

Pubmed ID: 28881833

Associated grants

  • Agency: NIDCR NIH HHS, United States
    Id: K08 DE020140
  • Agency: NCCIH NIH HHS, United States
    Id: P01 AT004418
  • Agency: NCI NIH HHS, United States
    Id: P30 CA014599
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR000430

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