Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 38, Pages 26290-26301Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.572560
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Funding
- National Basic Research Program of China [2012CB967903, 2012CB966800, 2013CB945600]
- National Natural Science Foundation of China [81270438, 81130038, 81372189]
- Science and Technology Commission of Shanghai Municipality (Pujiang program)
- Shanghai Health Bureau Key Discipline and Specialty Foundation [J50208]
- Shanghai Education Committee Key Discipline and Specialty Foundation
- KC Wong Foundation
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Tremendous efforts have been made to elucidate the molecular mechanisms that control the specification of definitive endoderm cell fate in gene knockout mouse models and ES cell (ESC) differentiation models. However, the impact of the unfolded protein response (UPR), because of the stress of the endoplasmic reticulum on endodermal specification, is not well addressed. We employed UPR-inducing agents, thapsigargin and tunicamycin, in vitro to induce endodermal differentiation of mouse ESCs. Apart from the endodermal specification of ESCs, Western blotting demonstrated the enhanced phosphorylation of Smad2 and nuclear translocation of beta-catenin in ESC-derived cells. The inclusion of the endoplasmic reticulum stress inhibitor tauroursodeoxycholic acid to the induction cultures prevented the differentiation of ESCs into definitive endodermal cells even when Activin A was supplemented. Also, the addition of the TGF-beta inhibitor SB431542 and the Wnt/beta-catenin antagonist IWP-2 negated the endodermal differentiation of ESCs mediated by thapsigargin and tunicamycin. These data suggest that the activation of the UPR appears to orchestrate the induction of the definitive endodermal cell fate of ESCs via both the Smad2 and beta-catenin signaling pathways. The prospective regulatory machinery may be helpful for directing ESCs to differentiate into definitive endodermal cells for cellular therapy in the future.
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