Hhex Is Necessary for the Hepatic Differentiation of Mouse ES Cells and Acts via Vegf Signaling.
Hhex Is Necessary for the Hepatic Differentiation of Mouse ES Cells and Acts via Vegf Signaling.
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HHEX对于小鼠ES细胞的肝分化和通过VEGF信号的作用是必需的。
DOI：
10.1371/journal.pone.0146806
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Bogue CW
中科院分区：
文献类型：
--
作者：
Arterbery AS;Bogue CW
阐明干细胞分化为肝细胞的分子机制对于理解正常发育过程以及优化用于治疗的功能性肝细胞的产生都是至关重要的。我们进行了小鼠胚胎干细胞（mESC）的体外分化，在同源异型盒基因Hhex中具有无效突变，并且显示Hhex-/-mESC不能从定形内胚层（Sox 17 +/Foxa 2+）分化为肝内胚层（Alb+/Dlk+）。此外，与Hhex+/+细胞相比，肝培养物引起Hhex-/-细胞中Vegfa mRNA表达增加>7倍。此外，我们在早期Hhex+/+肝培养物中鉴定了VEGFR 2 +/ALB+/CD 34-。这些细胞在Hhex-/-培养物中不存在。最后，通过操纵Hhex和Vegfa表达，表达的获得和丧失实验显示，Hhex与支持肝分化的Vegf信号传导途径的活性呈反比关系。总之，我们的研究结果表明，Hhex抑制VEGF信号在小鼠胚胎干细胞的肝分化过程中允许独立于内皮细胞的细胞类型的自主调节Vegfr 2活性。
Elucidating the molecular mechanisms involved in the differentiation of stem cells to hepatic cells is critical for both understanding normal developmental processes as well as for optimizing the generation of functional hepatic cells for therapy. We performed in vitro differentiation of mouse embryonic stem cells (mESCs) with a null mutation in the homeobox gene Hhex and show that Hhex-/- mESCs fail to differentiate from definitive endoderm (Sox17+/Foxa2+) to hepatic endoderm (Alb+/Dlk+). In addition, hepatic culture elicited a >7-fold increase in Vegfa mRNA expression in Hhex-/- cells compared to Hhex+/+ cells. Furthermore, we identified VEGFR2+/ALB+/CD34- in early Hhex+/+ hepatic cultures. These cells were absent in Hhex-/- cultures. Finally, through manipulation of Hhex and Vegfa expression, gain and loss of expression experiments revealed that Hhex shares an inverse relationship with the activity of the Vegf signaling pathway in supporting hepatic differentiation. In summary, our results suggest that Hhex represses Vegf signaling during hepatic differentiation of mouse ESCs allowing for cell-type autonomous regulation of Vegfr2 activity independent of endothelial cells.
双能小鼠胚胎肝（BMEL）细胞自发表达PDX1和NGN3，但在HES1下调时不会进一步进行胰腺分化。
影响因子：
1.8
作者：
Delisle JC;Martignat L;Bach JM;Bösch S;Louzier V
通讯作者：
Louzier V