A predictive model of asymmetric morphogenesis from 3D reconstructions of mouse heart looping dynamics

Garrec, Jean-François Le; Domínguez, Jorge N.; Desgrange, Audrey; Ivanovitch, Kenzo; Raphaël, Etienne; Bangham, Jenny; Torres, Miguel; Coen, Enrico; Mohun, Timothy J.; Meilhac, Sigolène M.

doi:10.7554/elife.28951

Cited by 78 publications

(159 citation statements)

References 85 publications

(128 reference statements)

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“…4A). These further developed into denser crescent-like structures with beating areas, leading to beating epithelial protrusions on the anterior portion of the gastruloids at around 168 h. Similar to mouse embryos (Ivanovitch et al, 2017;Le Garrec et al;Tyser et al, 2016), these phenotypes could be observed in gastruloids within 24 h, and could be aligned to progressive morphological stages of embryonic cardiac development between E7.5 and E8.5 (Fig. 4B).…”

Section: In Vitro Cardiac Development Occurs Through Establishment Ofmentioning

confidence: 60%

Embryonic organoids recapitulate early heart organogenesis

Rossi

Boni²,

Guiet

et al. 2019

Preprint

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Organoids are powerful models for studying tissue development, physiology, and disease. However, current culture systems disrupt the inductive tissue-tissue interactions needed for the complex morphogenetic processes of native organogenesis. Here we show that mouse embryonic stem cells (mESCs) can be coaxed to robustly undergo the fundamental steps of early heart organogenesis with an in vivo-like spatiotemporal fidelity. These axially patterned embryonic organoids support the generation of cardiovascular progenitors, as well as first and second heart field compartments. The cardiac progenitors self-organize into an anterior domain reminiscent of a cardiac crescent before forming a beating cardiac tissue near a primitive gutlike tube, from which it is separated by an endocardial-like layer. These findings unveil the surprising morphogenetic potential of mESCs to execute key aspects of organogenesis through the coordinated development of multiple tissues. This platform could be an excellent tool for studying heart development in unprecedented detail and throughput.

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Section: In Vitro Cardiac Development Occurs Through Establishment Ofmentioning

confidence: 60%

Embryonic organoids recapitulate early heart organogenesis

Rossi

Boni²,

Guiet

et al. 2019

Preprint

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show abstract

“…Nodal expression in the lateral plate mesoderm has been previously reported at 3-6 somite stages (Vincent et al, 2004). However, we found that somitogenesis is not synchronised with heart morphogenesis (Le Garrec et al, 2017), so we re-analysed Nodal expression within the context of heart looping stages. By RT-qPCR of the cardiac region, we found expression of Nodal at E8.5c-d ( Fig.…”

Section: Nodal Is Transiently Active Before Heart Looping At E85c-ementioning

confidence: 88%

“…From 3D (dimensions) reconstructions in the mouse embryo, we have previously characterised the spatiotemporal dynamics of heart looping, and established specific staging criteria. A model for a heart-specific random generator of asymmetry was proposed (Le Garrec et al, 2017). We showed that the heart tube grows between fixed poles, which is compatible with a buckling mechanism, able to generate random deformations.…”

Section: Introductionmentioning

confidence: 83%

“…Within the framework of the model of heart looping that we have proposed previously (Le Garrec et al, 2017), we analysed whether the identified parameters are affected. Heart looping depends on the buckling of the heart tube, growing between fixed poles.…”

Section: Existence Of a Random Generator Of Asymmetry Independent Of mentioning

confidence: 99%

“…Clonal analyses of myocardial cells have shown a differential origin of the pulmonary trunk and aorta from left and right precursors respectively (Lescroart et al, 2010;. In keeping with the spiralling of the great arteries in the mature heart, the outflow tract undergoes a rightward rotation (Bajolle et al, 2006), which follows that of the arterial pole during heart looping (Le Garrec et al, 2017). Regionalisation of the outflow tract prefigures the separation of the great arteries, as marked by Sema3c (Théveniau-Ruissy et al, 2008).…”

Section: Introductionmentioning

confidence: 97%

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Transient Nodal signalling in left precursors coordinates opposed asymmetries shaping the heart loop

Desgrange

Garrec

Bernheim

et al. 2019

Preprint

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The secreted factor Nodal has been shown to be a major left determinant. Although it is associated with severe congenital heart defects, its role in heart morphogenesis has remained poorly understood. Here, we report that Nodal is transiently active in precursors of the mouse heart tube poles, before the morphological changes of heart looping. In conditional mutants, we show that Nodal is not required to initiate asymmetric morphogenesis. We provide evidence of a heart-specific random generator of asymmetry that is independent of Nodal. Using 3D quantifications and simulations, we demonstrate that Nodal functions as a bias of this mechanism: it is required to amplify and coordinate opposed left-right asymmetries at the heart tube poles, thus generating a robust helical shape. We identify downstream effectors of Nodal signalling, regulating asymmetries in cell proliferation, cell differentiation and extra-cellular matrix composition. Our work provides novel insight into how Nodal regulates asymmetric organogenesis.

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An integrative multiscale view of early cardiac looping

Ebrahimi

Bradley

Hunter

2021

WIREs Mechanisms of Disease

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The heart is the first organ to form and function during the development of an embryo. Heart development consists of a series of events believed to be highly conserved in vertebrates. Development of heart begins with the formation of the cardiac fields followed by a linear heart tube formation. The straight heart tube then undergoes a ventral bending prior to further bending and helical torsion to form a looped heart. The looping phase is then followed by ballooning, septation, and valve formation giving rise to a four-chambered heart in avians and mammals. The looping phase plays a central role in heart development.Successful looping is essential for proper alignment of the future cardiac chambers and tracts. As aberrant looping results in various congenital heart diseases, the mechanisms of cardiac looping have been studied for several decades by various disciplines. Many groups have studied anatomy, biology, genetics, and mechanical processes during heart looping, and have proposed multiple mechanisms. Computational modeling approaches have been utilized to examine the proposed mechanisms of the looping process. Still, the exact underlying mechanism(s) controlling the looping phase remain poorly understood.Although further experimental measurements are obviously still required, the need for more integrative computational modeling approaches is also apparent in order to make sense of the vast amount of experimental data and the complexity of multiscale developmental systems. Indeed, there needs to be an iterative interaction between experimentation and modeling in order to properly find the gap in the existing data and to validate proposed hypotheses.

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A predictive model of asymmetric morphogenesis from 3D reconstructions of mouse heart looping dynamics

Cited by 78 publications

References 85 publications

Embryonic organoids recapitulate early heart organogenesis

Embryonic organoids recapitulate early heart organogenesis

Transient Nodal signalling in left precursors coordinates opposed asymmetries shaping the heart loop

An integrative multiscale view of early cardiac looping

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