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Cardioids reveal self-organizing principles of human cardiogenesis

Pablo Hofbauer, Stefan Jahnel, Nora Papai, Magdalena Giesshammer, Mirjam Penc, Katherina Tavernini, Nastasja Grdseloff, Christy Meledeth, Alison Deyett, Clara Schmidt, Claudia Ctortecka, Šejla Šalic, Maria Novatchkova, Sasha Mendjan
doi: https://doi.org/10.1101/2020.07.06.189431
Pablo Hofbauer
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Stefan Jahnel
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Nora Papai
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Magdalena Giesshammer
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Mirjam Penc
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Katherina Tavernini
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Nastasja Grdseloff
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
3Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
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Christy Meledeth
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Alison Deyett
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Clara Schmidt
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Claudia Ctortecka
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Šejla Šalic
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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Maria Novatchkova
2Institute of Molecular Pathology (IMP), Vienna Biocenter 1, 1030 Vienna, Austria
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Sasha Mendjan
1Institute of Molecular Biotechnology (IMBA), Dr. Bohr Gasse 3, 1030 Vienna, Austria
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  • For correspondence: sasha.mendjan@imba.oeaw.ac.at
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SUMMARY

Organoids that self-organize into tissue-like structures have transformed our ability to model human development and disease. To date, all major organs can be mimicked using self-organizing organoids with the notable exception of the human heart. Here, we established self-organizing cardioids from human pluripotent stem cells that intrinsically specify, pattern and morph into chamber-like structures containing a cavity. Cardioid complexity can be controlled by signaling that instructs the separation of cardiomyocyte and endothelial layers, and by directing epicardial spreading, inward migration and differentiation. We find that cavity morphogenesis is governed by a mesodermal WNT-BMP signaling axis and requires its target HAND1, a transcription factor linked to human heart chamber cavity defects. In parallel, a WNT-VEGF axis coordinates myocardial self-organization with endothelial patterning and specification. Human cardioids represent a powerful platform to mechanistically dissect self-organization and congenital heart defects, serving as a foundation for future translational research.

Highlights

  • - Cardioids form cardiac-like chambers with inner endothelial lining and interact with epicardium

  • - Cardioid self-organization and lineage complexity can be controlled by signaling

  • - WNT-BMP signaling directs cavity formation in self-organized cardioids via HAND1

  • - WNT-VEGF coordinate endothelial patterning with myocardial cavity morphogenesis

Competing Interest Statement

The Institute for Molecular Biotechnology (IMBA) filed a patent application (EP20164637.9) with P. Hofbauer, S. Jahnel, N. Papai and S. Mendjan named as inventors. The application covers the methods for generation of different types of cardiac organoids (cardioids) included in this manuscript.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE148025

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 06, 2020.
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Cardioids reveal self-organizing principles of human cardiogenesis
Pablo Hofbauer, Stefan Jahnel, Nora Papai, Magdalena Giesshammer, Mirjam Penc, Katherina Tavernini, Nastasja Grdseloff, Christy Meledeth, Alison Deyett, Clara Schmidt, Claudia Ctortecka, Šejla Šalic, Maria Novatchkova, Sasha Mendjan
bioRxiv 2020.07.06.189431; doi: https://doi.org/10.1101/2020.07.06.189431
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Cardioids reveal self-organizing principles of human cardiogenesis
Pablo Hofbauer, Stefan Jahnel, Nora Papai, Magdalena Giesshammer, Mirjam Penc, Katherina Tavernini, Nastasja Grdseloff, Christy Meledeth, Alison Deyett, Clara Schmidt, Claudia Ctortecka, Šejla Šalic, Maria Novatchkova, Sasha Mendjan
bioRxiv 2020.07.06.189431; doi: https://doi.org/10.1101/2020.07.06.189431

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