低氧通过上调Wnt5a促进人胚胎干细胞向生血内皮细胞分化

胚胎的早期发育是在低氧条件下进行的，低氧环境在胚胎血管发生及造血发育中起着重要作用，低氧条件能促进胚胎干细胞在体外向内皮细胞和造血细胞的分化，但低氧条件对造血细胞产生的具体作用及相应机制尚不清楚．本研究利用人Es细胞向造血祖细胞定向分化体系，发现低氧环境可以促进CD31＋TIE2＋造血内皮祖细胞的产生，2天后造血内皮祖细胞开始表达终生造血基因．进一步研究发现，低氧能够上调Wnt5a的表达，干涉Wnt5a能够抑制低氧环境对生血内皮细胞分化的促进作用．在正常氧环境下加入Wnt5a产生促进生血内皮细胞分化的效应，该效应与低氧处理促进生血内皮细胞产生的作用相似．本研究首次证明了低氧通过上调Wnt5a的表达促进人Es细胞向生血内皮细胞的分化，为ES细胞向生血内皮细胞的分化及造血祖细胞分化的研究提供了新的线索．

Hypoxia Enhances the Differentiation of Hemogenic Endothelial Cells from Human Embryonic Stem Cells through Up-regulating Wnt5a Signal

Hypoxia plays important roles in embryonic vasculogenesis, hematopoiesis and has been applied in embryonic stem （ES） cell differentiation towards endothelial and hematopoietic cells. However, the precise role of hypoxia and its underlying mechanisms on the hematopoietic differentiation remains unclear. In this study, we found that hypoxia enhanced the generation of CD31＋TIE2＋ hemato-vascular progenitor cells from human ES-derived mesoderm cells, and followed by the gene expression of definitive hematopoietic genes after two days. Importantly, we found that hypoxia functioned on the hemato-vascular progenitor differentiation by stimulating the enhanced secretion of Wnt5a, while Wnt5a disrupted with shRNA inhibited the generation of hemato-vascular progenitor cells. Wnt5a added in normoxia promoted the generation of hemato-vascular progenitor ceils and this effect is similar to that generated by hypoxia to enhance the generation of hemato-vascular progenitor cells. In conclusion, our study is the first to identify that hypoxia enhanced the generation of hemato-vascular progenitor cells from human ES cell-derived mesoderm through up-regulating Wnt5a signal. This finding provides new clues for studying the mechanism of committed differentiation of hemogenic endothelium and HPC/HSCs from human ES cells.