Precardiac organoids form two heart fields via Bmp/Wnt signaling

Andersen, Peter; Tampakakis, Emmanouil; Jimenez, Dennisse V.; Kannan, Suraj; Miyamoto, Matthew; Shin, Hyun Soo; Saberi, Amir; Murphy, Sheldon D.; Sulistio, Edrick; Chelko, Stephen P.; Kwon, Chulan

doi:10.1038/s41467-018-05604-8

Cited by 113 publications

(109 citation statements)

References 71 publications

(101 reference statements)

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“…We show that embryonic organoids can be stimulated to form a cardiac portion that involves key developmental hallmarks such as the generation and spatial arrangement of early cardiac progenitors and first and second heart field compartmentalization. Of note, precardiac spheroids were previously shown to generate progenitors with FHF and SHF identity, however, these spheroids did not develop an organized structure (Andersen et al, 2018). In contrast, in our model system, these populations emerged in an embryo-like, spatially organized structure.…”

Section: Discussioncontrasting

confidence: 63%

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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: Discussioncontrasting

confidence: 63%

“…3D). To corroborate the presence of progenitor populations from both heart fields in our organoids, we used a recently published protocol (Andersen et al, 2018) for FACS-isolating SHF progenitors based on the expression of the C-X-C chemokine receptor type 4 (CXCR4) (Fig. 3E).…”

Section: In Vitro Cardiac Development Entails First and Second Heart mentioning

confidence: 99%

Embryonic organoids recapitulate early heart organogenesis

Rossi

Boni²,

Guiet

et al. 2019

Preprint

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“…The growth factors bone morphogenetic protein 4 (BMP4) and activin A have frequently been used as alternatives to small molecule Wnt signaling manipulation since they are the endogenous morphogens that pattern the early embryonic cardiogenic mesoderm and determine heart field specification in vivo 27,[45][46][47] . We wondered whether BMP4 and activin A, in combination with our small molecule Wnt activation/inhibition protocol, could synergistically improve the ability of hHOs to recapitulate cardiac development in vitro.…”

Section: Bmp4 and Activin A Improve Heart Organoid Chamber Formation mentioning

confidence: 99%

“…Organoids have proven particularly useful to study unapproachable disease states in humans or for which animal models are not readily available. While organoids have been used very successfully to model a wide range of organ system (colon, pancreas, kidney) 16,17,[19][20][21][22][23] and disease conditions (cancer, host-microbe interactions) 17,[24][25][26][27][28] , their application to cardiovascular studies has been sorely lacking. Cardiac organoid fabrication methods were published as early as 2007 29 , and made noticeable progress in the recent years [30][31][32][33][34][35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

Generation of Heart Organoids Modeling Early Human Cardiac Development Under Defined Conditions

Ball

Wasserman

et al. 2020

Preprint

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Cardiovascular-related disorders are a significant worldwide health problem. Cardiovascular disease (CVD) is the leading cause of death in developed countries, making up a third of the mortality rate in the US 1 . Congenital heart defects (CHD) affect ~1% of all live births 2 , making it the most common birth defect in humans. Current technologies provide some insight into how these disorders originate but are limited in their ability to provide a complete overview of disease pathogenesis and progression due to their lack of physiological complexity. There is a pressing need to develop more faithful organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here, we report the most faithful in vitro organoid model of human cardiovascular development to date using human pluripotent stem cells (hPSCs). Our protocol is highly efficient, scalable, shows high reproducibility and is compatible with high-throughput approaches. Furthermore, our hPSC-based heart organoids (hHOs) showed very high similarity to human fetal hearts, both morphologically and in cell-type complexity. hHOs were differentiated using a two-step manipulation of Wnt signaling using chemical inhibitors and growth factors in completely defined media and culture conditions. Organoids were successfully derived from multiple independent hPSCs lines with very similar efficiency. hHOs started beating at ~6 days, were mostly spherical and grew up to ~1 mm in diameter by day 15 of differentiation. hHOs developed sophisticated, interconnected internal chambers and confocal analysis for cardiac markers revealed the presence of all major cardiac lineages, including cardiomyocytes (TNNT2 + ), epicardial cells (WT1 + , TJP + ), cardiac fibroblasts (THY1 + , VIM + ), endothelial cells (PECAM1 + ), and endocardial cells (NFATC1 + ). Morphologically, hHOs developed well-defined epicardial and adjacent myocardial regions and presented a distinct vascular plexus as well as endocardial-lined microchambers. RNA-seq time-course analysis of hHOs, monolayer differentiated iPSCs and fetal human hearts revealed that hHOs recapitulate human fetal heart tissue development better than previously described differentiation protocols 3,4 . hHOs allow higher-order interaction of distinct heart tissues for the first time and display biologically relevant physical and topographical 3D cues that closely resemble the human fetal heart. Our model constitutes a powerful novel tool for discovery and translational studies in human cardiac development and disease.

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“…The endocardial cells (ECs) are a spatially restricted cell population by de novo vasculogenesis from cardiogenic progenitors distinct from the hemangioblasts that give rise to other endothelial subtypes. A growing body of studies support the notion that the endocardial cells are derived from Isl1 + /Kdr + multipotent progenitors via cardiogenic mesoderm cells expressing T + /Mesp1 + (Andersen et al, 2018;Nakano et al, 2016;Hoffman et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Generation of cardiac valve endocardial like cells from human pluripotent stem cells

Sun

Cheng

Geng

et al. 2020

Preprint

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The cardiac valvular endothelial cells (VECs) are an ideal cell source that could be used for the fabrication of the next generation tissue-engineered cardiac valves (TEVs). However, few studies have been focused on the derivation of this important cell type. Here we describe a chemically defined xeno-free method for generating VEC-like cells from human pluripotent stem cells (hPSCs) through an intermediate endocardium stage. HPSCs were initially specified to KDR + /ISL1 + multipotent cardiac progenitor cells (CPCs), followed by differentiation into endocardial progenitors under the combined treatment with VEGFA, BMP4 and bFGF. In the presence of VEGFA, BMP4 and TGFb, valve endocardial progenitor cells (VEPs) were efficiently derived from endocardial progenitors without a sorting step.Mechanistically, administration of TGFb and BMP4 may specify the VEP fate by facilitating the expression of key transcription factors ETV2 and NFATc1 at the immediate early stage and by activating Notch signaling at the later stage. Notch activation is likely an important part of VEP induction. HPSC-derived VEPs exhibited morphological, molecular and functional similarities to that of the primary VECs isolated from normal human aortic valves. When hPSC-derived VEPs were seeded onto the surface of the de-cellularized porcine aortic valve (DCV) matrix scaffolds, they exhibited higher proliferation and survival potential than the primary VECs. Our results suggest that hPSC-derived VEPs could serve as as a potential platform for the study of valve development, and as starting materials for the construction of the next generation TEVs. Highlights:

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Precardiac organoids form two heart fields via Bmp/Wnt signaling

Cited by 113 publications

References 71 publications

Embryonic organoids recapitulate early heart organogenesis

Embryonic organoids recapitulate early heart organogenesis

Generation of Heart Organoids Modeling Early Human Cardiac Development Under Defined Conditions

Generation of cardiac valve endocardial like cells from human pluripotent stem cells

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