RT Journal Article
SR Electronic
T1 Multi-chamber cardioids unravel human heart development and cardiac defects
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.14.499699
DO 10.1101/2022.07.14.499699
A1 Clara Schmidt
A1 Alison Deyett
A1 Tobias Ilmer
A1 Aranxa Torres Caballero
A1 Simon Haendeler
A1 Lokesh Pimpale
A1 Michael A. Netzer
A1 Lavinia Ceci Ginistrelli
A1 Martina Cirigliano
A1 Estela Juncosa Mancheno
A1 Daniel Reumann
A1 Katherina Tavernini
A1 Steffen Hering
A1 Pablo Hofbauer
A1 Sasha Mendjan
YR 2022
UL http://biorxiv.org/content/early/2022/07/16/2022.07.14.499699.abstract
AB 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.HIGHLIGHTS- Mesoderm induction and patterning signals specify aSHF, pSHF, and FHF progenitors- Cardiac progenitors sort, co-develop and functionally connect in multi-chamber cardioids- Multi-chamber cardioids coordinate contraction propagation and share a lumen- Multi-chamber platform dissects genetic (ISL1, TBX5, FOXF1) and teratogenic defectsCompeting Interest StatementThe 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.