lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling.
lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling.
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lncRNA H19通过Notch信号介导BMP9诱导的间充质干细胞（MSC）成骨分化
DOI：
10.18632/oncotarget.18655
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发表时间：
2017-08-08
期刊：
影响因子：
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通讯作者：
He TC
中科院分区：
文献类型：
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作者：
Liao J;Yu X;Hu X;Fan J;Wang J;Zhang Z;Zhao C;Zeng Z;Shu Y;Zhang R;Yan S;Li Y;Zhang W;Cui J;Ma C;Li L;Yu Y;Wu T;Wu X;Lei J;Wang J;Yang C;Wu K;Wu Y;Tang J;He BC;Deng ZL;Luu HH;Haydon RC;Reid RR;Lee MJ;Wolf JM;Huang W;He TC
间充质干细胞（MSCs）是一种多能祖细胞，可以自我更新并分化成多个谱系。MSCs的成骨分化是一个精心策划的过程，受多种信号通路的调节。我们之前已经证明BMP9是最有效的成骨因子之一。然而，BMP9调控成骨细胞分化的分子机制尚不完全清楚。越来越多的证据表明，非编码rna （ncRNAs）可能在许多生理和/或病理过程中发挥重要的调节作用。在本研究中，我们研究了lncRNA H19在bmp - 9调控的MSCs成骨分化中的作用。我们证明H19在BMP9刺激MSCs的早期阶段急剧上调，随后迅速下降并逐渐恢复到基础水平。这一过程与bmp9诱导的成骨标志物表达有关。有趣的是，MSCs中组成型H19的表达或沉默型H19的表达在体外和体内都会显著损害bmp9诱导的成骨分化，而这一分化可通过Notch信号的激活有效地恢复。无论是组成型H19表达还是沉默型H19表达都会导致一组mirna的表达增加，这些mirna预计会靶向Notch配体和受体。因此，这些结果表明lncRNA H19通过调节Notch靶向mirna作为BMP9信号传导的重要介质。我们的研究结果表明，在bmp9诱导的MSCs成骨分化中，协调良好的lncRNA H19双相表达可能是必不可少的，而失调的H19表达可能会损害正常的成骨过程，导致骨肿瘤的发生等致病过程。
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.