TY - JOUR T1 - Cardioids reveal self-organizing principles of human cardiogenesis JF - bioRxiv DO - 10.1101/2020.07.06.189431 SP - 2020.07.06.189431 AU - Pablo Hofbauer AU - Stefan Jahnel AU - Nora Papai AU - Magdalena Giesshammer AU - Mirjam Penc AU - Katherina Tavernini AU - Nastasja Grdseloff AU - Christy Meledeth AU - Alison Deyett AU - Clara Schmidt AU - Claudia Ctortecka AU - Šejla Šalic AU - Maria Novatchkova AU - Sasha Mendjan Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/06/2020.07.06.189431.abstract N2 - 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 morphogenesisCompeting Interest StatementThe 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. ER -