Sox11-modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs
Sox11-modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs
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DOI：
10.1096/fj.14-254169
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发表时间：
2015-04-01
期刊：
影响因子：
4.8
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Xu, Liangliang;Huang, Shuo;Li, Gang
间充质干细胞（MSCs）是一种很有前途的组织工程细胞资源。sry相关的高迁移性群盒11 （Sox11）在神经发育和器官发生中起着关键作用。在本研究中，我们研究了Sox11在调节MSCs三期分化（成骨、脂肪和软骨形成）和迁移中的作用，并利用大鼠开放性股骨骨折模型探讨了系统给药Sox11修饰的MSCs对骨折愈合的影响。我们的研究结果表明，Sox11过表达增加了MSCs的三年期分化和迁移，以及氧化应激下的细胞活力。通过裸鼠异位成骨实验证实了Sox11对成骨的影响。此外，我们发现Sox11可以激活MSCs中骨形态发生蛋白(BMP)/Smad信号通路。通过双荧光素酶报告基因实验，我们还证实了Sox11可以转录激活矮子相关转录因子2 （Runx2）和CXC趋化因子受体4 （CXCR4）的表达。BMP/Smad信号通路的激活与Runx2、CXCR4的表达可能具有协同作用，这在很大程度上促成了Sox11对MSC命运决定和迁移的影响。最后，通过大鼠开放性股骨骨折模型，我们发现大量稳定表达Sox11的MSCs迁移到骨折部位，促进骨折愈合。综上所述，我们的研究表明Sox11是MSC分化和迁移的重要调节因子，Sox11修饰的MSCs可能具有加速骨折愈合的临床意义，可以减少延迟愈合或不愈合。
Mesenchymal stem cells (MSCs) are a promising cell resource for tissue engineering. Sry-related high-mobility group box 11 (Sox11) plays critical roles in neural development and organogenesis. In the present study, we investigated the role of Sox11 in regulating trilineage differentiation (osteogenesis, adipogenesis, and chondrogenesis) and migration of MSCs, and explored the effect of systemically administrated Sox11-modified MSCs on bone fracture healing using the rat model of open femur fracture. Our results demonstrated that Sox11 overexpression increased the trilineage differentiation and migration of MSCs, as well as cell viability under oxidative stress. The effect of Sox11 on osteogenesis was confirmed by ectopic bone formation assay conducted in nude mice. In addition, we found that Sox11 could activate the bone morphogenetic protein (BMP)/Smad signaling pathway in MSCs. By dual-luciferase reporter assay, we also demonstrated that Sox11 could transcriptionally activate runt-related transcription factor 2 (Runx2) and CXC chemokine receptor-4 (CXCR4) expression. The activation of the BMP/Smad signaling pathway and Runx2, CXCR4 expression may have a synergic effect, which largely contributed to the effect of Sox11 on MSC fate determination and migration. Finally, using an open femur fracture model in rats, we found that a larger number of MSCs stably expressing Sox11 migrated to the fracture site and improved bone fracture healing. Taken together, our study shows that Sox11 is an important regulator of MSC differentiation and migration, and Sox11-modified MSCs may have clinical implication for accelerating bone fracture healing, which can reduce the delayed unions or nonunions.