BMP9-induced osteoblastic differentiation requires functional Notch signaling in mesenchymal stem cells.
BMP9-induced osteoblastic differentiation requires functional Notch signaling in mesenchymal stem cells.
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DOI：
10.1038/s41374-018-0087-7
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
He TC
中科院分区：
文献类型：
--
作者：
Cui J;Zhang W;Huang E;Wang J;Liao J;Li R;Yu X;Zhao C;Zeng Z;Shu Y;Zhang R;Yan S;Lei J;Yang C;Wu K;Wu Y;Huang S;Ji X;Li A;Gong C;Yuan C;Zhang L;Liu W;Huang B;Feng Y;An L;Zhang B;Dai Z;Shen Y;Luo W;Wang X;Huang A;Luu HH;Reid RR;Wolf JM;Thinakaran G;Lee MJ;He TC
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）是一种多能祖细胞，可分化为包括成骨细胞在内的多种细胞系。骨髓间充质干细胞的成骨分化是一个级联反应，重演了胚胎骨骼发育过程中发生的大部分（如果不是全部的话）分子事件，这是由包括骨形态发生蛋白（BMP）在内的许多信号通路调节的。通过对成骨活性的全面分析，我们先前证明了BMP 9是体外和体内诱导MSC形成骨的最有效的BMP。然而，作为研究最少的BMPs之一，BMP9诱导的成骨信号的基本介质仍然是难以捉摸的。在这里，我们表明，BMP9诱导的成骨信号在MSC需要完整的Notch信号。虽然Notch受体和配体的表达在MSC中是容易检测到的，但Notch抑制剂和显性阴性Notch1在体外有效地抑制BMP 9诱导的成骨分化和体内异位骨形成。Notch途径的遗传破坏严重损害BMP9诱导的MSC成骨分化和异位骨形成。此外，虽然BMP 9诱导的早期应答基因的表达不受缺陷性Notch信号传导的影响，但BMP 9在成骨分化的中间阶段上调Notch受体和配体的表达。总之，这些结果表明，Notch信号传导可能在协调BMP 9诱导的MSC成骨分化中发挥重要作用。骨形态发生蛋白（BMP）9是间充质干细胞成骨分化的有效诱导剂，但BMP 9诱导成骨的介质仍然难以捉摸。在这里，作者表明Notch1信号的抑制有效地减少了BMP 9诱导的骨生成。Notch途径的遗传破坏严重损害BMP 9诱导的骨形成。因此，这些结果表明，Notch信号传导可能在协调成骨分化中发挥重要作用。
Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into multiple lineages including osteoblastic lineage. Osteogenic differentiation of MSCs is a cascade that recapitulates most, if not all, of the molecular events occurring during embryonic skeletal development, which is regulated by numerous signaling pathways including bone morphogenetic proteins (BMPs). Through a comprehensive analysis of the osteogenic activity, we previously demonstrated that BMP9 is the most potent BMP for inducing bone formation from MSCs both in vitro and in vivo. However, as one of the least studied BMPs, the essential mediators of BMP9-induced osteogenic signaling remain elusive. Here we show that BMP9-induced osteogenic signaling in MSCs requires intact Notch signaling. While the expression of Notch receptors and ligands are readily detectable in MSCs, Notch inhibitor and dominant-negative Notch1 effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic bone formation in vivo. Genetic disruption of Notch pathway severely impairs BMP9-induced osteogenic differentiation and ectopic bone formation from MSCs. Furthermore, while BMP9-induced expression of early-responsive genes is not affected by defective Notch signaling, BMP9 upregulates the expression of Notch receptors and ligands at the intermediate stage of osteogenic differentiation. Taken together, these results demonstrate that Notch signaling may play an essential role in coordinating BMP9-induced osteogenic differentiation of MSCs. Bone morphogenetic protein (BMP) 9 is a potent inducer of osteogenic differentiation from mesenchymal stem cells, but the mediators of BMP9-induced osteogenesis remain elusive. Here, the authors show that inhibition of Notch1 signaling effectively diminishes BMP9-induced osteogenesis. Genetic disruption of Notch pathway severely impairs BMP9-induced bone formation. Thus, these results demonstrate that Notch signaling may play an essential role in coordinating osteogenic differentiation.
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