Universität zu Köln

Rao, Jyoti ORCID: 0000-0002-7624-930X, Pfeiffer, Martin J., Frank, Stefan, Adachi, Kenjiro, Piccini, Ilaria, Quaranta, Roberto ORCID: 0000-0002-8365-4952, Arauzo-Bravo, Marcos, Schwarz, Juliane, Schade, Dennis ORCID: 0000-0002-5515-1821, Leidel, Sebastian ORCID: 0000-0002-0523-6325, Schoeler, Hans R., Seebohm, Guiscard and Greber, Boris ORCID: 0000-0002-9404-7293 (2016). Stepwise Clearance of Repressive Roadblocks Drives Cardiac Induction in Human ESCs. Cell Stem Cell, 18 (3). S. 341 - 354. CAMBRIDGE: CELL PRESS. ISSN 1875-9777

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Abstract

Cardiac induction requires stepwise integration of BMP and WNT pathway activity. Human embryonic stem cells (hESCs) are developmentally and clinically relevant for studying the poorly understood molecular mechanisms downstream of these cascades. We show that BMP and WNT signaling drive cardiac specification by removing sequential roadblocks that otherwise redirect hESC differentiation toward competing fates, rather than activating a cardiac program per se. First, BMP and WNT signals pattern mesendoderm through cooperative repression of SOX2, a potent mesoderm antagonist. BMP signaling promotes miRNA-877 maturation to induce SOX2 mRNA degradation, while WNT-driven EOMES induction transcriptionally represses SOX2. Following mesoderm formation, cardiac differentiation requires inhibition of WNT activity. We found that WNT inhibition serves to restrict expression of anti-cardiac regulators MSX1 and CDX2/1. Conversely, their simultaneous disruption partially abrogates the requirement for WNT inactivation. These results suggest that human cardiac induction depends on multi-stage repression of alternate lineages, with implications for deriving expandable cardiac stem cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rao, Jyoti UNSPECIFIED orcid.org/0000-0002-7624-930X UNSPECIFIED Pfeiffer, Martin J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Frank, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Adachi, Kenjiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Piccini, Ilaria UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaranta, Roberto UNSPECIFIED orcid.org/0000-0002-8365-4952 UNSPECIFIED Arauzo-Bravo, Marcos UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Schade, Dennis UNSPECIFIED orcid.org/0000-0002-5515-1821 UNSPECIFIED Leidel, Sebastian UNSPECIFIED orcid.org/0000-0002-0523-6325 UNSPECIFIED Schoeler, Hans R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seebohm, Guiscard UNSPECIFIED UNSPECIFIED UNSPECIFIED Greber, Boris UNSPECIFIED orcid.org/0000-0002-9404-7293 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-281721
DOI:	10.1016/j.stem.2015.11.019
Journal or Publication Title:	Cell Stem Cell
Volume:	18
Number:	3
Page Range:	S. 341 - 354
Date:	2016
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1875-9777
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EMBRYONIC STEM-CELLS; BETA-CATENIN; PROGENITOR CELLS; DIFFERENTIATION; SPECIFICATION; MESODERM; TRANSCRIPTION; GASTRULATION; PLURIPOTENCY; ACTIVATION Multiple languages Cell & Tissue Engineering; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28172