期刊
STEM CELL RESEARCH
卷 10, 期 3, 页码 489-502出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.scr.2012.04.002
关键词
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资金
- George F. Straub Trust Fund of the Hawaii Community Foundation Medical Research Grant [11ADVC-49271]
- Johns Hopkins Center for Alternatives [2012-11]
- COBRE grants from the National Center for Research Resources [5P20RR024206-05]
- National Institute of General Medical Sciences from the National Institutes of Health [8P20GM103457-05]
- Cell and Molecular Biology Graduate Program at the University of Hawaii
Human embryonic stem cells (hESCs) can self-renew and become all three germ layers. Nodal/Activin signaling specifies developmental status in hESCs: moderate Nodal/Activin signaling maintains pluripotency, while enhancement and inhibition promote definitive endoderm (DE) and neuroectoderm (NE) development, respectively. However, how modulation of Nodal/Activin signaling influences developmental competence and commitment toward specific lineages is still unclear. Here, we showed that enhancement of Nodal/Activin signaling for 4 days was necessary and sufficient to upregulate DE markers, while it diminished the upregulation of NE markers by inhibition of Nodal/Activin signaling. This suggests that after 4 days of enhanced Nodal/Activin signaling, hESCs are committed to the DE lineage and have lost competence toward the NE lineage. In contrast, inhibition of Nodal/Activin signaling using LY364947 for 2 days was sufficient to impair competence toward the DE lineage, although cells were still able to activate LEFTY1 and NODAL, direct targets of Nodal/Activin signaling: Expression analyses indicated that the levels of pluripotency regulators NANOG and POU5F1 were significantly diminished by 2 days of LY364947 treatment, although the expression of NANOG, but not POU5F1, was restored immediately upon Activin A treatment. Thus, downregulation of POU5F1 coincided with the abrogation of DE competence caused by inhibition of Nodal/Activin signaling. (C) 2012 Elsevier B.V. All rights reserved.
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