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Cell Stem Cell. 2011 Mar 4;8(3):326-34. doi: 10.1016/j.stem.2011.01.001.

FGF2 sustains NANOG and switches the outcome of BMP4-induced human embryonic stem cell differentiation.

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Morgridge Institute for Research, Madison, WI 53715-7365, USA.


Here, we show that as human embryonic stem cells (ESCs) exit the pluripotent state, NANOG can play a key role in determining lineage outcome. It has previously been reported that BMPs induce differentiation of human ESCs into extraembryonic lineages. Here, we find that FGF2, acting through the MEK-ERK pathway, switches BMP4-induced human ESC differentiation outcome to mesendoderm, characterized by the uniform expression of T (brachyury) and other primitive streak markers. We also find that MEK-ERK signaling prolongs NANOG expression during BMP-induced differentiation, that forced NANOG expression results in FGF-independent BMP4 induction of mesendoderm, and that knockdown of NANOG greatly reduces T induction. Together, our results demonstrate that FGF2 signaling switches the outcome of BMP4-induced differentiation of human ESCs by maintaining NANOG levels through the MEK-ERK pathway.

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