The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fate
The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fate
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DOI：
10.1038/leu.2015.74
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发表时间：
2015-08-01
期刊：
影响因子：
11.4
通讯作者：
Menendez, P.
中科院分区：
文献类型：
--
作者：
Ayllon, V.;Bueno, C.;Menendez, P.
Notch信号传导对于确定的造血是必不可少的，但其在人类胚胎造血中的作用在很大程度上是未知的。我们发现，在hESC中，Notch配体DLL 4的表达在造血分化过程中被诱导。我们发现DLL 4仅在双能血内皮祖细胞（HEP）的亚群中表达，并分离其造血与内皮潜能。我们在克隆水平和通过转录组分析证明，DLL 4（高）HEP富含内皮潜能，而DLL 4（低/-）HEP致力于造血谱系，尽管两个群体仍然含有双能细胞。此外，DLL 4刺激增强HEP的造血分化并增加克隆生成造血祖细胞的量。共聚焦显微镜分析的整个分化胚状体显示，DLL 4高的HEP位于靠近DLL 4（低/-）的HEP，并在基础上的CD 45+细胞的集群，类似于主动脉内造血集群中发现的小鼠胚胎。我们提出了一种人胚胎造血模型，其中生血内皮内的DLL 4（低/-）细胞接收来自DLL 4（高）细胞的Notch激活信号，导致内皮向造血转变并分化为CD 45+造血细胞。
Notch signaling is essential for definitive hematopoiesis, but its role in human embryonic hematopoiesis is largely unknown. We show that in hESCs the expression of the Notch ligand DLL4 is induced during hematopoietic differentiation. We found that DLL4 is only expressed in a sub-population of bipotent hematoendothelial progenitors (HEPs) and segregates their hematopoietic versus endothelial potential. We demonstrate at the clonal level and through transcriptome analyses that DLL4(high) HEPs are enriched in endothelial potential, whereas DLL4(low/-) HEPs are committed to the hematopoietic lineage, albeit both populations still contain bipotent cells. Moreover, DLL4 stimulation enhances hematopoietic differentiation of HEPs and increases the amount of clonogenic hematopoietic progenitors. Confocal microscopy analysis of whole differentiating embryoid bodies revealed that DLL4high HEPs are located close to DLL4(low/-) HEPs, and at the base of clusters of CD45+ cells, resembling intra-aortic hematopoietic clusters found in mouse embryos. We propose a model for human embryonic hematopoiesis in which DLL4(low/-) cells within hemogenic endothelium receive Notch-activating signals from DLL4(high) cells, resulting in an endothelial-to-hematopoietic transition and their differentiation into CD45+ hematopoietic cells.