Mesenchymal stem cells regulate angiogenesis according to their mechanical environment
Mesenchymal stem cells regulate angiogenesis according to their mechanical environment
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DOI：
10.1634/stemcells.2006-0432
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Duda, Georg N.
中科院分区：
文献类型：
--
作者：
Kasper, Grit;Dankert, Niels;Duda, Georg N.
在骨折和骨缺损的愈合过程中，MSCs在很大程度上推动了组织的再生。在体内和体外，MSCs都被证明能促进血管生成。血管生成是大组织重建的先决条件。本研究探讨了机械负荷对MSCs促血管生成能力的影响。结果表明，在二维管形成和三维球体萌发实验中，机械刺激的条件培养液与未刺激的MSCs相比，显著促进了血管生成。特别是，内皮细胞的增殖增加，而不是迁移或黏附。血管生成的促进依赖于成纤维细胞生长因子受体1(FGFR1)信号。此外，血管内皮细胞生长因子受体(VEGFR)酪氨酸激酶的阻断抑制了对小管形成的刺激。对不同可溶性血管生成调节因子表达水平的筛选显示，机械刺激使基质金属蛋白酶2、转化生长因子β1和碱性成纤维细胞生长因子表达增加，而血管内皮生长因子表达增加。综上所述，MSCs的机械负荷似乎导致了血管生成的旁分泌刺激，很可能是通过调节几个血管生成分子的网络来实现的。潜在的机制似乎依赖于FGFR和VEGFR信号级联，并可能通过与其他途径的额外串扰来调节。
In fracture and bone defect healing, MSCs largely drive tissue regeneration. MSCs have been shown to promote angiogenesis both in vivo and in vitro. Angiogenesis is a prerequisite to large tissue reconstitution. The present study investigated how mechanical loading of MSCs influences their proangiogenic capacity. The results show a significant enhancement of angiogenesis by conditioned media from mechanically stimulated compared with unstimulated MSCs in two-dimensional tube formation and three-dimensional spheroid sprouting assays. In particular, proliferation but not migration or adhesion of endothelial cells was elevated. Promotion of angiogenesis was dependent upon fibroblast growth factor receptor 1 (FGFR1) signaling. Moreover, stimulation of tube formation was inhibited by vascular endothelial growth factor receptor (VEGFR) tyrosine kinase blocking. Screening for the expression levels of different soluble regulators of angiogenesis revealed an enrichment of matrix metalloprotease 2, transforming growth factor beta 1, and basic fibroblast growth factor but not of vascular endothelial growth factor in response to mechanical stimulation. In conclusion, mechanical loading of MSCs seems to result in a paracrine stimulation of angiogenesis, most likely by the regulation of a network of several angiogenic molecules. The underlying mechanism appears to be dependent on the FGFR and VEGFR signaling cascades and might be mediated by an additional cross-talk with other pathways.