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Published online
doi:10.1083/jcb.200901040
The Journal of Cell Biology, Vol. 186, No. 5, 665-673
The Rockefeller University Press, 0021-9525 $30.00
© Stefanovic et al.
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Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate



Sonia Stefanovic1, Nesrine Abboud1, Stéphanie Désilets1, David Nury1, Chad Cowan2, and Michel Pucéat1

1 Institut National de la Santé et de la Recherche Médicale (INSERM), Avenir Team, Stem Cells and Cardiogenesis, Evry 91058, France
2 Stowers Medical Institute, Center for Regenerative Medicine and Technology, Cardiovascular Research Center, Boston, MA 02114

Correspondence to Michel Pucéat: michel.puceat{at}inserm.fr

Oct4 exerts a dose-dependent dual action, as both a gatekeeper for stem cell pluripotency and in driving cells toward specific lineages. Here, we identify the molecular mechanism underlying this dual function. BMP2- or transgene-induced Oct4 up-regulation drives human embryonic and induced pluripotent stem cells to become cardiac progenitors. When embryonic stem cell pluripotency is achieved, Oct4 switches from the Sox2 to the Sox17 promoter. This switch allows the cells to turn off the pluripotency Oct4-Sox2 loop and to turn on the Sox17 promoter. This powerful process generates a subset of endoderm-expressing Sox17 and Hex, both regulators of paracrine signals for cardiogenesis (i.e., Wnt, BMP2) released into the medium surrounding colonies of embryonic stem cells. Our data thus reveal a novel molecular Oct4- and Sox17-mediated mechanism that disrupts the stem cell microenvironment favoring pluripotency to provide a novel paracrine endodermal environment in which cell lineage is determined and commits the cells to a cardiogenic fate.

Abbreviations used in this paper: CM, conditioned medium; cTnT, cardiac troponin T; EB, embryoid body; ESC, embryonic stem cell; HCC, high content cell; HESC, human ESC; iPSC, induced pluripotent stem cell; Oct4-iA-OEC, Oct4-iA–overexpressing cells; p, promoter; RT-Q-PCR, real-time quantitative PCR; TF, transcription factor.

© 2009 Stefanovic et al.
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