Embryonic organoids recapitulate early heart organogenesis

Rossi, G.; Boni, Andrea; Guiet, Romain; Girgin, Mehmet; Kelly, Robert G.

doi:10.1101/802181

Cited by 10 publications

(8 citation statements)

References 47 publications

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“…These have proven immensely useful to measure contraction force, perform compound screens and model structural muscle and arrhythmogenic disorders. Similarly, mouse and human PSC-derived 3D cardiac models including spherical aggregates (microtissues) of CMs and other cardiac cell types (Giacomelli et al, 2017;Richards et al, 2020), have been reported as promising tools for drug discovery; and embryoid models (Rossi et al, 2019;Silva et al, 2020) as providing insights into germ layer interactions in early organogenesis. However, existing models do not recapitulate cardiac-specific self-organizing patterning and morphogenesis to acquire in vivo-like architecture, and they are therefore limited as models of early human cardiogenesis and congenital heart disease.…”

Section: Introductionmentioning

confidence: 99%

Cardioids reveal self-organizing principles of human cardiogenesis

Hofbauer

Jahnel

Pápai

et al. 2020

Preprint

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SUMMARYOrganoids 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 morphogenesis

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Section: Introductionmentioning

confidence: 99%

Cardioids reveal self-organizing principles of human cardiogenesis

Hofbauer

Jahnel

Pápai

et al. 2020

Preprint

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“…Fig.7. Analysis of single-cell RNAseq datasets from SBR Gastruloids highlights two "endoderm" clusters (A) Top: UMAP representation of the dataset fromRossi et al (2019). The two clusters attributed as "early endoderm" (13) and "mature endoderm" (4) are highlighted in gold and beige respectively.…”

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confidence: 99%

In vitroendoderm emergence and self-organisation in the absence of extraembryonic tissues and embryonic architecture

Vianello

2020

Preprint

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The endoderm is the cell lineage which gives rise in the 1 embryo to the organs of the respiratory and gastrointestinal 2 system. In the mouse this may be the germ layer with the 3 strongest association with its extraembryonic counterpart. 4 Uniquely indeed, endodermal tissue does not just derive from 5 descendants of the embryo proper (the epiblast) but instead 6 arises from their gradual incorporation into an extraembryonic 7 substrate (the visceral endoderm). Given the configuration of 8 the early embryo, such a paradigm requires epiblast endoder-9 mal progenitors to negotiate embryonic compartments with 10 very diverse epithelial character, a developmental contingency 11 reflected by the fact that key early endodermal markers such 12 as Foxa2 and Sox17 have been consistently found to be em-13 bedded within gene programmes involved in epithelialisation. 14 15 To explore the underlying cell biology of embryonic endo-16 derm precursors, and to explore the relationship between 17 endoderm development, epithelial identity, and extraembry-18 onic mixing, we leveraged Gastruloids, in vitro models of 19 early development. These self-organising three-dimensional 20 aggregates of mouse embryonic stem cells do not possess an 21 extraembryonic component, nor do they appear to display 22 typical tissue architecture. Yet, they generate cells expressing 23 endodermal markers. By tracking these cells throughout in 24 vitro development, we highlight a persistent and uninterrupted 25 pairing between epithelial and endodermal identity, with 26 FoxA2+/Sox17+ endoderm progenitors never transitioning 27 through mesenchymal intermediates and never leaving the 28 epithelial compartment in which they arise. We also docu-29 ment the dramatic morphogenesis of these progenitors into a 30 macroscopic epithelial primordium extending along the entire 31 anterior-posterior axis of the Gastruloid, patterned into broad 32 domains of gene expression. Corollarily we thus also reveal 33 an underappreciated epithelial component in Gastruloids, 34 and thus the spontaneous emergence in vitro of stratified 35 architectures and germ layer compartmentalisation. 36 gastruloid | endoderm development | epithelium | self-organisation 37 Correspondence: stefano.vianello@epfl.ch and matthias.lutolf@epfl.ch 38 76 fiers somehow oxymoronic, "extraembryonic" cells (i.e. cells 77 that segregated away from the epiblast early on even before 78 implantation) also contribute to the embryo, and specifically 79 to its endoderm-derived tissues. Indeed, the epiblast is not 80 isolated from other tissues within the conceptus, and it is 81 actually enveloped by a thin epithelium of so-called Visceral 82

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“…Upon administration of cardiogenic factors FGF, VEGF and ascorbic acid, mGastruloids reproducibly recapitulate cardiogenesis at their anterior end, giving rise a vascular-like network, first and second heart fields as well as ultimately a beating structure, resembling an actual embryonic heart [158]. Moreover, mGastruloids generated not only from mESCs but also from XEN cells exhibit increased cell type diversity and develop neural-tube-like structures.…”

Section: Mouse -Gastruloidsmentioning

confidence: 96%

Studying evolution of the primary body axis in vivo and in vitro

Anlaş¹,

Trivedi²

2020

Preprint

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The metazoan body plan is established during early embryogenesis via collective cell rearrangements and evolutionarily conserved gene networks, as part of a process commonly referred to as gastrulation. While substantial progress has been achieved in terms of characterizing the embryonic development of several model organisms, underlying principles of many early patterning processes nevertheless remain enigmatic. Despite the diversity of (pre-)gastrulating embryo and adult body shapes across the animal kingdom, the body axes, which are arguably the most fundamental features, generally remain identical between phyla. Recently there has been a renewed appreciation of ex vivo and in vitro embryo-like systems to model early embryonic patterning events. Here, we briefly review key examples and propose that similarities in morphogenesis as well as associated gene expression dynamics may reveal an evolutionarily conserved developmental mode as well as provide further insights into the role of external or extraembryonic cues in shaping the early embryo. In summary, we argue that embryo-like systems can be employed to inform previously uncharted aspects of animal body plan evolution as well as associated patterning rules.

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Embryonic organoids recapitulate early heart organogenesis

Cited by 10 publications

References 47 publications

Cardioids reveal self-organizing principles of human cardiogenesis

Cardioids reveal self-organizing principles of human cardiogenesis

In vitroendoderm emergence and self-organisation in the absence of extraembryonic tissues and embryonic architecture

Studying evolution of the primary body axis in vivo and in vitro

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