Signal Transduction
Smad2 Is Essential for Maintenance of the Human and Mouse Primed Pluripotent Stem Cell State*

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Human embryonic stem cells and mouse epiblast stem cells represent a primed pluripotent stem cell state that requires TGF-β/activin signaling. TGF-β and/or activin are commonly thought to regulate transcription through both Smad2 and Smad3. However, the different contributions of these two Smads to primed pluripotency and the downstream events that they may regulate remain poorly understood. We addressed the individual roles of Smad2 and Smad3 in the maintenance of primed pluripotency. We found that Smad2, but not Smad3, is required to maintain the undifferentiated pluripotent state. We defined a Smad2 regulatory circuit in human embryonic stem cells and mouse epiblast stem cells, in which Smad2 acts through binding to regulatory promoter sequences to activate Nanog expression while in parallel repressing autocrine bone morphogenetic protein signaling. Increased autocrine bone morphogenetic protein signaling caused by Smad2 down-regulation leads to cell differentiation toward the trophectoderm, mesoderm, and germ cell lineages. Additionally, induction of Cdx2 expression, as a result of decreased Smad2 expression, leads to repression of Oct4 expression, which, together with the decreased Nanog expression, accelerates the loss of pluripotency. These findings reveal that Smad2 is a unique integrator of transcription and signaling events and is essential for the maintenance of the mouse and human primed pluripotent stem cell state.

Background:

TGF-β signaling is required for primed pluripotency, but the roles of Smad2 and Smad3 have not been well defined.

Results:

Smad2, but not Smad3, has a role in pluripotency by activating Nanog expression and repressing BMP signaling.

Conclusion:

Smad2 is essential in the maintenance of pluripotency.

Significance:

The roles of Smad2 and Smad3 need to be distinguished in the regulation of pluripotency by TGF-β signaling.

Bone Morphogenetic Protein (BMP)
Cell Differentiation
Smad Transcription Factor
Stem Cells
Transforming Growth Factor β (TGFβ)
Nanog
Pluripotency

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*

This work was supported, in whole or in part, by National Institutes of Health Grant R21 HL0923494 (to R. D.). This work was also supported by CIRM New Stem Cell Lines Grant RL-100669 (to M. R.-S.).

This article contains supplemental Tables S1 and S2.

1

Supported by postdoctoral fellowships from the Union Internationale Contre le Cancer, the Uehara Foundation, and an award from the Program in Breakthrough Basic Research at University of California at San Francisco.

2

Supported by a postdoctoral fellowship from the American Heart Association, a University of California at San Francisco core exploratory award, and a Muscular Dystrophy Association development grant.