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1.
Cell ; 186(25): 5587-5605.e27, 2023 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-38029745

RESUMEN

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 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 mutations, teratogens, and drugs cause compartment-specific defects in the developing human heart.


Asunto(s)
Cardiopatías , Ventrículos Cardíacos , Corazón , Humanos , Transcriptoma/genética , Línea Celular , Regulación del Desarrollo de la Expresión Génica , Cardiopatías/genética , Cardiopatías/metabolismo
2.
Cell ; 184(12): 3299-3317.e22, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34019794

RESUMEN

Organoids capable of forming tissue-like structures have transformed our ability to model human development and disease. With the notable exception of the human heart, lineage-specific self-organizing organoids have been reported for all major organs. 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 developmental heart chamber defects. Upon cryoinjury, cardioids initiated a cell-type-dependent accumulation of extracellular matrix, an early hallmark of both regeneration and heart disease. Thus, human cardioids represent a powerful platform to mechanistically dissect self-organization, congenital heart defects and serve as a foundation for future translational research.


Asunto(s)
Corazón/embriología , Organogénesis , Organoides/embriología , Activinas/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Calcio/metabolismo , Línea Celular , Linaje de la Célula , Pollos , Células Endoteliales/citología , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Fibroblastos/citología , Proteína Homeótica Nkx-2.5/metabolismo , Humanos , Masculino , Mesodermo/embriología , Modelos Biológicos , Miocardio/metabolismo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Wnt/metabolismo
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