Extracellular signal-regulated kinases (ERKs) have many important functions during embryogenesis. However, their role in embryonic stem (ES) cells is controversial. Previous studies reported that, in contrast to mouse ES cells, human ES cells differentiate if ERK1/2 is inhibited. We reexamined the role of ERK1/2 in human ES cells using a chemically defined culture system and found that when ERK1/2 is blocked with specific chemical inhibitors, neural and mesendodermal differentiation is prevented, but cells become sensitive to BMP-induced differentiation. Inhibition of ERK1/2 significantly reduced the clonogenicity of human ES cells by preventing cell adhesion and survival. When this negative effect was avoided, we were able to maintain human ES cell self-renewal for more than 3months in the presence of ERK1/2 inhibitors in a chemically defined culture system containing FGF2 and activin A but no BMP4. Our results suggest that the functional outcome of FGF/ERK1/2 signaling in human ES cells is influenced by the relative levels of activin A/TGFbeta and BMP activity. Moreover, activation of ERK1/2 in human ES cells is required for proper neural and mesendodermal differentiation. In contrast to mouse ES cells, a low level of BMP4 is sufficient to initiate extraembryonic differentiation when ERK1/2 is inhibited.
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