Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)
Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)
复制标题
Notch 信号传导通过促进间充质干细胞 (MSC) 中的成骨-血管生成偶联过程来增强 BMP9 诱导的骨形成
DOI：
10.1159/000471945
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发表时间：
2017-01-01
影响因子：
--
通讯作者：
Huang, Wei
中科院分区：
文献类型：
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作者：
Liao, Junyi;Wei, Qiang;Huang, Wei
间充质干细胞（Mesenchymal stem cells，MSCs）是一种多能性祖细胞，可分化为包括骨在内的多种细胞系。成功的骨形成需要MSC的成骨和血管生成偶联。在这里，我们调查，如果同时激活BMP 9和Notch信号产生有效的成骨-血管生成的MSC耦合。方法：采用最近鉴定的永生化小鼠脂肪源性祖细胞（iMAD）作为MSC来源。通过腺病毒载体表达转基因BMP 9、NICD和dnNotch 1。qPCR和荧光定量化学法检测基因表达。通过体外实验和体内异位骨形成模型评估成骨活性。结果：BMP 9上调iMAD中Notch受体和配体的表达。Notch 1的组成型活性形式NICD 1在体外和体内均增强BMP 9诱导的成骨分化，这被Notch 1 dnNotch 1的显性阴性形式有效抑制。BMP 9和NICD 1转导的MSC与生物相容性支架一起植入，产生了具有广泛血管化的高度成熟的骨。NICD 1增强BMP 9诱导的异位骨中iMAD和Vegfa中关键血管生成调节因子的表达，这被dnNotch 1减弱。结论：Notch信号通路可能在BMP 9诱导的成骨和血管生成中发挥重要作用。可以想象的是，BMP 9和Notch通路的同时激活应该有效地将MSC的成骨和血管生成偶联用于成功的骨组织工程。
Background/Aims: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. Methods: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. Results: BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. Conclusion: Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It’s conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.