Signaling hierarchy regulating human endothelial cell development.
Signaling hierarchy regulating human endothelial cell development.
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DOI：
10.1161/atvbaha.109.184200
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
Hirschi KK
中科院分区：
文献类型：
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作者：
Kelly MA;Hirschi KK
我们目前对哺乳动物内皮细胞分化调控的认识主要来源于对小鼠胚胎发育的研究。然而，控制人内皮细胞发育的独特机制和信号层次尚不清楚，因此在这些研究中进行了探索。使用人胚胎干细胞作为模型系统，我们能够通过与OP 9骨髓基质细胞共培养可重复且稳健地产生分化的内皮细胞。我们发现，在小鼠中的研究相反，bFGF和VEGF对人类血管发生的启动没有特异性的影响。然而，外源性Ihh促进内皮细胞分化，如通过具有鹅卵石形态的细胞的增加的产生所证明的，所述鹅卵石形态共表达多种内皮特异性基因和蛋白，形成管腔，并表现出DiI-AcLDL摄取。使用Noggin或BMP 4抑制BMP信号传导，特别是使用中和抗体抑制内皮细胞形成;而向用刺猬抑制剂环巴胺处理的细胞中加入rhBMP 4拯救了内皮细胞发育。我们的研究表明，Ihh通过BMP信号传导促进多能hES细胞向人内皮细胞分化，为人类临床治疗提供了适用于调节人内皮细胞形成和血管再生的新见解。
Our present knowledge of the regulation of mammalian endothelial cell differentiation has been largely derived from studies of mouse embryonic development. However, unique mechanisms and hierarchy of signals that govern human endothelial cell development are unknown and, thus, explored in these studies. Using human embryonic stem cells as a model system, we were able to reproducibly and robustly generate differentiated endothelial cells via co-culture on OP9 marrow stromal cells. We found that, in contrast to studies in the mouse, bFGF and VEGF had no specific effects on the initiation of human vasculogenesis. However, exogenous Ihh promoted endothelial cell differentiation, as evidenced by increased production of cells with cobblestone morphology that co-express multiple endothelial-specific genes and proteins, form lumens, and exhibit DiI-AcLDL uptake. Inhibition of BMP signaling using Noggin or BMP4, specifically, using neutralizing antibodies suppressed endothelial cell formation; whereas, addition of rhBMP4 to cells treated with the hedgehog inhibitor cyclopamine rescued endothelial cell development. Our studies revealed that Ihh promoted human endothelial cell differentiation from pluripotent hES cells via BMP signaling, providing novel insights applicable to modulating human endothelial cell formation and vascular regeneration for human clinical therapies.