Unfolded Protein Response Is Required for the Definitive Endodermal Specification of Mouse Embryonic Stem Cells via Smad2 and beta-catenin Signaling [Cell Biology]

August 4th, 2014 by Xu, H., Tsang, K. S., Wang, Y., Chan, J. C. N., Xu, G., Gao, W.-Q.

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 ESCs differentiation models, however the impact of unfolded protein response (UPR) due to the stress of the endoplasmic reticulum (ER) on the endodermal specification is not well addressed. We employed UPR-inducing agents, thapsigargin (TG) and tunicamycin (TM), 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 ESCs-derived cells. The inclusion of ER stress inhibitor tauroursodeoxycholic acid (TUDCA) to the induction cultures prevented the differentiation of ESCs to definitive endodermal cells even when Activin A was supplemented. Besides, the addition of TGF-beta inhibitor SB431542 and Wnt/beta-catenin antagonist IWP-2 negated the endodermal differentiation of ESCs mediated by TG and TM. These data suggest that the activation of UPR appears to orchestrate the induction of definitive endodermal cell fate of ESCs via both 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.
  • Posted in Journal of Biological Chemistry, Publications
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