Differentiation of human embryonic stem cells to HOXA+ hemogenic vasculature that resembles the aorta-gonad-mesonephros
Differentiation of human embryonic stem cells to HOXA+ hemogenic vasculature that resembles the aorta-gonad-mesonephros
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DOI：
10.1038/nbt.3702
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发表时间：
2016-11-01
影响因子：
46.9
通讯作者：
Elefanty, Andrew G.
中科院分区：
文献类型：
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作者：
Ng, Elizabeth S.;Azzola, Lisa;Elefanty, Andrew G.
从人类多能细胞中产生造血干细胞的能力将使许多生物医学应用成为可能。我们发现，与人类脐带血CD34（+）细胞相比，源自人类胚胎干细胞（hESCs）的自旋胚状体中的造血CD34（+）细胞缺乏HOXA表达，表明不正确的中胚层模式。利用报告细胞hESC细胞系追踪发生在发育过程中的内皮细胞（SOX17）向造血细胞（RUNX1C）的转变，我们发现WNT和ACTIVIN信号的同时调节产生具有HOXA表达的CD34（+）造血细胞，其表达更接近脐带血。培养物产生类似于主动脉样SOX17（+）血管网络，从中产生RUNX1C（+）血细胞，类似于主动脉-性腺-中肾（AGM）的造血。新生的CD34（+）造血细胞与从人AGM中分选的相应细胞在细胞表面受体、信号分子和转录因子的表达上相似。我们的研究结果提供了一种在体外模拟人类造血的关键早期阶段的方法，用于从hESCs中产生agm衍生的造血谱系。
The ability to generate hematopoietic stem cells from human pluripotent cells would enable many biomedical applications. We find that hematopoietic CD34(+) cells in spin embryoid bodies derived from human embryonic stem cells (hESCs) lack HOXA expression compared with repopulation-competent human cord blood CD34(+) cells, indicating incorrect mesoderm patterning. Using reporter hESC lines to track the endothelial (SOX17) to hematopoietic (RUNX1C) transition that occurs in development, we show that simultaneous modulation of WNT and ACTIVIN signaling yields CD34(+) hematopoietic cells with HOXA expression that more closely resembles that of cord blood. The cultures generate a network of aorta-like SOX17(+) vessels from which RUNX1C(+) blood cells emerge, similar to hematopoiesis in the aorta-gonad-mesonephros (AGM). Nascent CD34(+) hematopoietic cells and corresponding cells sorted from human AGM show similar expression of cell surface receptors, signaling molecules and transcription factors. Our findings provide an approach to mimic in vitro a key early stage in human hematopoiesis for the generation of AGM-derived hematopoietic lineages from hESCs.