Multi-chamber cardioids unravel human heart development and cardiac defects

The number one cause of human fetal death are defects in heart development. Because the human embryonic heart is inaccessible, and the impacts of mutations, drugs, and environmental factors on the specialized functions of different heart compartments are not captured by in vitro models, determining...

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Published inbioRxiv
Main Authors Schmidt, Clara, Deyett, Alison, Ilmer, Tobias, Aranxa Torres Caballero, Haendeler, Simon, Pimpale, Lokesh, Netzer, Michael A, Lavinia Ceci Ginistrelli, Cirigliano, Martina, Estela Juncosa Mancheno, Reumann, Daniel, Tavernini, Katherina, Hering, Steffen, Hofbauer, Pablo, Mendjan, Sasha
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.07.2022
Subjects
Biotechnology
Embryogenesis
Environmental factors
Fetuses
Gene expression
Heart
Ontogeny
Patent applications
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Summary:The number one cause of human fetal death are defects in heart development. Because the human embryonic heart is inaccessible, and the impacts of mutations, drugs, and environmental factors on the specialized functions of different heart compartments are not captured by in vitro models, determining the underlying causes is difficult. Here, we established a human cardioid platform that recapitulates the development of all major embryonic heart compartments, including right and left ventricles, atria, outflow tract, and atrioventricular canal. By leveraging both 2D and 3D differentiation, we efficiently generated progenitor subsets with distinct first, anterior, and posterior second heart field identities. This advance enabled the reproducible generation of cardioids with compartment-specific in vivo-like gene expression profiles, morphologies, and functions. We used this platform to unravel the ontogeny of signal and contraction propagation between interacting heart chambers and dissect how genetic and environmental factors cause region-specific defects in the developing human heart. Competing Interest Statement The Institute for Molecular Biotechnology (IMBA) filed a patent application on multi-chamber cardioids with C.S., A.D. T.I., and S.M. named as inventors. P.H. and S.M. are co-founders of HeartBeat.bio AG, an IMBA spin-off company, that aims to develop a cardioid drug discovery platform.
DOI:10.1101/2022.07.14.499699