Nodal/Activin Signaling Predicts Human Pluripotent Stem Cell Lines Prone to Differentiate Toward the Hematopoietic Lineage
Nodal/Activin Signaling Predicts Human Pluripotent Stem Cell Lines Prone to Differentiate Toward the Hematopoietic Lineage
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DOI：
10.1038/mt.2010.179
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发表时间：
2010-12-01
影响因子：
12.4
通讯作者：
Menendez, Pablo
中科院分区：
文献类型：
--
作者：
Ramos-Mejia, Veronica;Melen, Gustavo J.;Menendez, Pablo
不同的人类多能干细胞（hPSC）系之间的谱系特异性分化潜力不同，因此非常需要前瞻性地了解哪些hPSC系在某一谱系中表现出最高的分化潜力。我们比较了14个人胚胎干细胞(hESC)/诱导多能干细胞（iPSC）系的造血潜能。分析不同时间点的造血祖细胞、原始血细胞和成熟血细胞的出现情况以及集落形成单位（CFU）电位。在向血液分化的倾向方面，我们观察到不同的人造血干细胞之间存在显著差异：一些人造血干细胞表现出良好的血液分化潜力，而另一些人几乎没有表现出血液分化能力。相关研究显示CFU电位与造血祖细胞和原始而非成熟血细胞密切相关。中胚层和造血转录因子的表达与造血起始和成熟效率均无相关性。微阵列研究显示造血潜能好与造血潜能差的人造血干细胞之间存在不同的基因表达谱。虽然神经外胚层相关基因在易于造血分化的人造血干细胞中下调，但许多节点/激活素信号成员上调，这表明该信号预测了具有良好血液分化潜力的人造血干细胞系。淋巴结/激活素信号传导与造血分化潜能之间的关联通过功能损失和功能获得分析得到证实。我们的数据加强了前瞻性比较研究的价值，这些研究旨在确定不同hPSC之间谱系特异性分化的潜力，并表明节点/激活素信号似乎可以预测那些易于造血特异性的hPSC系。
Lineage-specific differentiation potential varies among different human pluripotent stem cell (hPSC) lines, becoming therefore highly desirable to prospectively know which hPSC lines exhibit the highest differentiation potential for a certain lineage. We have compared the hematopoietic potential of 14 human embryonic stem cell (hESC)/induced pluripotent stem cell (iPSC) lines. The emergence of hemogenic progenitors, primitive and mature blood cells, and colony-forming unit (CFU) potential was analyzed at different time points. Significant differences in the propensity to differentiate toward blood were observed among hPSCs: some hPSCs exhibited good blood differentiation potential, whereas others barely displayed blood-differentiation capacity. Correlation studies revealed that the CFU potential robustly correlates with hemogenic progenitors and primitive but not mature blood cells. Developmental progression of mesoendodermal and hematopoietic transcription factors expression revealed no correlation with either hematopoietic initiation or maturation efficiency. Microarray studies showed distinct gene expression profile between hPSCs with good versus poor hematopoietic potential. Although neuroectoderm-associated genes were downregulated in hPSCs prone to hematopoietic differentiation many members of the Nodal/Activin signaling were upregulated, suggesting that this signaling predicts those hPSC lines with good blood-differentiation potential. The association between Nodal/Activin signaling and the hematopoietic differentiation potential was confirmed using loss- and gain-of-function functional assays. Our data reinforce the value of prospective comparative studies aimed at determining the lineage-specific differentiation potential among different hPSCs and indicate that Nodal/Activin signaling seems to predict those hPSC lines prone to hematopoietic specification.