GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells
GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells
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DOI：
10.1016/j.exphem.2015.09.007
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发表时间：
2016-01-01
影响因子：
2.6
通讯作者：
Hara, Takahiko
中科院分区：
文献类型：
--
作者：
Kitajima, Kenji;Nakajima, Marino;Hara, Takahiko
WNT/β-catenin信号通路促进人胚胎干细胞和人诱导多能干细胞(HiPSCs)向造血细胞和内皮细胞分化。瞬时加入GSK3β抑制剂(GSKi)可促进体外培养的hESCs/hiPSCs向内皮细胞分化。由于造血细胞和内皮细胞来源于共同的祖细胞(血源性内皮祖细胞[HEPs])，我们检测了短暂的GSKi处理对hPSCs向造血细胞分化的影响。我们发现，在HiPSC分化诱导开始时，短暂的GSKi处理改变了细胞的基因表达谱。GSKi处理显著上调了在发育中胚后中胚层表达的多种CDX/HOX基因。此外，在无血清和无基质的培养液中加入GSKi有效地诱导了HEPS，并且HEPS产生了不同的造血细胞和内皮细胞谱系。因此，瞬时的WNT/β-catenin信号触发CDX/Hox通路的激活，进而赋予分化的HiPSCs血源性后中胚层特性。这些数据加深了我们对人胚胎造血/内皮细胞发育的了解，并为诱导hPSCs向造血细胞分化提供了一种新的体外系统。版权所有(C)2016 ISEH-国际实验血液学学会。由爱思唯尔公司出版。
WNT/beta-CATENIN signaling promotes the hematopoietidendothelial differentiation of human embryonic stem cells and human induced pluripotent stem cells (hiPSCs). The transient addition of a GSK3 beta inhibitor (GSKi) has been found to facilitate in vitro endothelial cell differentiation from hESCs/hiPSCs. Because hematopoietic and endothelial cells are derived from common progenitors (hemogenic endothelial progenitors [HEPs]), we examined the effect of transient GSKi treatment on hematopoietic cell differentiation from hiPSCs. We found that transient GSKi treatment at the start of hiPSC differentiation induction altered the gene expression profile of the cells. Multiple CDX/HOX genes, which are expressed in the posterior mesoderm of developing embryos, were significantly upregulated by GSKi treatment. Further, inclusion of the GSKi in a serum- and stroma-free culture with chemically defined medium efficiently induced HEPs, and the HEPs gave rise to various lineages of hematopoietic and endothelial cells. Therefore, transient WNT/beta-CATENIN signaling triggers activation of the CDX/HOX pathway, which in turn confers hemogenic posterior mesoderm identity to differentiating hiPSCs. These data enhance our understanding of human embryonic hematopoietic/endothelial cell development and provide a novel in vitro system for inducing the differentiation of hematopoietic cells from hiPSCs. Copyright (C) 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.