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| Open AccessA patterned human primitive heart organoid model generated by pluripotent stem cell self-organization
Pluripotent stem cell-derived organoids can recapitulate significant hallmarks of human organ development and are becoming critical tools for human research. Here, the authors report significant technical steps for generating sophisticated synthetic human primitive heart organoids.
- Brett Volmert
- , Artem Kiselev
- & Aitor Aguirre
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| Open AccessDbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart
Catecholaminergic transmitters are critical signalling effectors known to be released by sympathetic nerves and adrenomedullary endocrine cells in response to physiological stress. In this paper, the authors demonstrate a uniquely distributed group of catecholaminergic cardiomyocytes with key regulatory roles in cardiac excitation conduction.
- Tianyi Sun
- , Alexander Grassam-Rowe
- & Ming Lei
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Article
| Open AccessCardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation
Cardiac regeneration is hindered by the limited division of cardiomyocytes. Here, the authors show that Arid1a drives maturation and limits proliferation through interaction with Yap. Suppression of Arid1a enhances proliferation after injury.
- Cornelis J. Boogerd
- , Ilaria Perini
- & Eva van Rooij
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| Open AccessEndothelial deletion of PTBP1 disrupts ventricular chamber development
Alternative splicing crucially affects various biological processes, however, its function in heart development is largely unknown. Here, the authors show an essential role of alternative splicing factor PTBP1 in ventricular chamber development.
- Hongyu Liu
- , Ran Duan
- & Yi-Han Chen
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Article
| Open AccessSingle-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell development
Cardiac neural crest must differentiate and migrate correctly to achieve proper cardiovascular development. Here, the authors use single cell analyses to show how these cells are altered non-autonomously by loss of Tbx1, the major gene for 22q11.2 deletion syndrome.
- Christopher De Bono
- , Yang Liu
- & Bernice E. Morrow
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Article
| Open AccessVariations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish
Bicuspid aortic valve (BAV) is the most common cardiac defect and although highly heritable, few causal mutations have been identified. Here, the authors identify variants in the poly-histidine repeat motif of HOXA1 and show that its disruption leads to BAV in mice.
- Gaëlle Odelin
- , Adèle Faucherre
- & Stéphane Zaffran
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Article
| Open AccessSingle-cell transcriptomic analysis identifies murine heart molecular features at embryonic and neonatal stages
A detailed multi-staged single cell atlas of heart development could improve our understanding of cell type diversification during cardiac development. Here, the authors generated a large dataset with cells from embryonic and neonatal hearts to identify the stage and chamber specific features in heart development.
- Wei Feng
- , Abha Bais
- & Guang Li
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| Open AccessActivation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration
The epicardium supports heart regeneration, though precisely how is unclear. Here the authors define an activated epicardial progenitor population as the source of essential cell types and paracrine factors for successful heart regeneration in zebrafish.
- Yu Xia
- , Sierra Duca
- & Jingli Cao
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Article
| Open AccessAllele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
The authors use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. The findings emphasize the importance of allele-specific insight into gene regulation in development, homeostasis and disease.
- Gayan I. Balasooriya
- & David L. Spector
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Article
| Open AccessA SOX17-PDGFB signaling axis regulates aortic root development
Little is known about the developmental causes of aortic root defects. Here the authors show that the inactivation of Sox17 in aortic root endothelium results in aortic root defects affecting aortic valve and coronary ostium.
- Pengfei Lu
- , Ping Wang
- & Bin Zhou
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| Open AccessCMYA5 establishes cardiac dyad architecture and positioning
Heart muscle cells exhibit exquisitely organized subcellular features that enable efficient and coordinated heart muscle contraction, but little is known about how it is achieved. Here the authors show that CMYA5 organizes cardiomyocyte calcium release units and aligns them to sarcomeres, leading to abnormal calcium release, cardiac dysfunction, and inability to tolerate pressure overload, when absent.
- Fujian Lu
- , Qing Ma
- & William T. Pu
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| Open AccessPhysiologic biomechanics enhance reproducible contractile development in a stem cell derived cardiac muscle platform
Investigations of human cardiac disease involving human pluripotent stem cell-derived cardiomyocytes are limited by the disorganized presentation of biomechanical cues resulting in cell immaturity. Here the authors develop a platform of micron-scale 2D cardiac muscle bundles to precisely deliver physiologic cues, improving reproducibility and throughput.
- Yao-Chang Tsan
- , Samuel J. DePalma
- & Adam S. Helms
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| Open AccessSelf-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.
- Yonatan R. Lewis-Israeli
- , Aaron H. Wasserman
- & Aitor Aguirre
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Matters Arising
| Open AccessReply to ‘Are atrial human pluripotent stem cell-derived cardiomyocytes ready to identify drugs that beat atrial fibrillation?’
- Assad Shiti
- , Idit Goldfracht
- & Lior Gepstein
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Article
| Open AccessSpatiotemporal single-cell RNA sequencing of developing chicken hearts identifies interplay between cellular differentiation and morphogenesis
Using single-cell and spatial transcriptomics in chicken hearts, here, the authors generate a census of cellular interactions from early to late four-chambered heart stage, identifying a distinct epicardial-mesenchymal cell population with a migratory phenotype.
- Madhav Mantri
- , Gaetano J. Scuderi
- & Iwijn De Vlaminck
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Article
| Open AccessQKI is a critical pre-mRNA alternative splicing regulator of cardiac myofibrillogenesis and contractile function
RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.
- Xinyun Chen
- , Ying Liu
- & Ning Sun
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Article
| Open AccessNkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
Here, the authors apply genetic fate mapping and temporal clonal analysis to study progenitor recruitment and network morphogenesis of murine cardiac Purkinje fibers. Additionally, they characterize how transcription factor dosage regulates cell fate divergence during distinct phases of this process.
- Caroline Choquet
- , Robert G. Kelly
- & Lucile Miquerol
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Article
| Open AccessFetal whole heart blood flow imaging using 4D cine MRI
Three-dimensional imaging of the fetal heart and quantification of blood flow in the surrounding vessels is very challenging because the heart is small and the fetus is free to move in the womb. Here, the authors demonstrate motion-corrected 4D flow MRI of the whole fetal heart and major vessels.
- Thomas A. Roberts
- , Joshua F. P. van Amerom
- & Joseph V. Hajnal
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Article
| Open AccessHierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
The processes regulating cardiomyocyte (CM) maturation are unclear. Here, the authors show that serum response factor regulates CM maturation only in neonatal CMs through stage-specific chromatin occupancy that affects cell size, sarcomere and transverse-tubule organization, and mitochondria
- Yuxuan Guo
- , Blake D. Jardin
- & William T. Pu
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| Open AccessContinuous addition of progenitors forms the cardiac ventricle in zebrafish
Late-differentiating second heart field progenitors contribute to atrium, ventricle, and outflow tract in the zebrafish heart but how remains unclear. Here, the authors image heart formation in transgenics based on the cardiopharyngeal gene tbx1 and show that progenitors are continuously added.
- Anastasia Felker
- , Karin D. Prummel
- & Christian Mosimann
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Article
| Open AccessGenome-wide analysis yields new loci associating with aortic valve stenosis
Aortic valve stenosis (AS) is the most common valvular heart disease. Here the authors identify two new AS loci that also associate with bicuspid aortic valve, aortic root diameter and/or coronary artery disease implicating both developmental abnormalities and atherosclerosis-like processes in AS.
- Anna Helgadottir
- , Gudmar Thorleifsson
- & Kari Stefansson
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| Open AccessAnalysis of cardiomyocyte clonal expansion during mouse heart development and injury
During cardiac tissue formation it is unclear whether newly generated myocytes originate from cardiac progenitor cells or from pre-existing cardiomyocytes. Here, the authors use a stochastic four-colour reporter system (Rainbow) to identify the source of new cardiomyocytes during mouse development.
- Konstantina-Ioanna Sereti
- , Ngoc B. Nguyen
- & Reza Ardehali
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| Open AccessLoss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration
During early postnatal development in mammals, cardiomyocytes exit the cell cycle, losing their regenerative capacity. Here the authors show that, following myocardial infarction, loss of microRNA-128 promotes cardiomyocyte proliferation and cardiac regeneration in adult mice partly via enhancing the expression of the chromatin modifier SUZ12.
- Wei Huang
- , Yuliang Feng
- & Yigang Wang
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Article
| Open AccessCardiogenic programming of human pluripotent stem cells by dose-controlled activation of EOMES
The T-box transcription factor eomesodermin (EOMES) acts both in endoderm specification as well as heart development, suggesting context-specific function. Here, the authors show that dose-controlled EOMES induction is sufficient for cardiogenic programming of human pluripotent stem cells.
- Martin J. Pfeiffer
- , Roberto Quaranta
- & Boris Greber
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Article
| Open AccessTbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration
It is not clear if it is the embryonic origin or anatomical location of cardiomyocytes that restrict their contribution to zebrafish heart regeneration. Here, the authors show a plasticity of embryonic precursors following tbx5a fate mapping and that trabecular cardiomyocytes help to rebuild the cortical myocardium.
- Héctor Sánchez-Iranzo
- , María Galardi-Castilla
- & Nadia Mercader
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Article
| Open AccessDistinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo
How the cardiac myocyte epigenome is rearranged during development, postnatal maturation and disease is not well understood. Here, the authors investigate the human cardiac myocyte epigenome during development and chronic heart failure and identify distinct epigenetic programs regulating these processes.
- Ralf Gilsbach
- , Martin Schwaderer
- & Lutz Hein
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Article
| Open AccessRETRACTED ARTICLE: REST regulates the cell cycle for cardiac development and regeneration
The mechanisms regulating cardiomyocyte proliferation during development and cardiac regeneration are incompletely understood. The authors show that the transcription factor REST regulates cardiomyocyte proliferation by binding and repressing the cell cycle inhibitor p21.
- Donghong Zhang
- , Yidong Wang
- & Bin Zhou
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Article
| Open AccessTransient cardiomyocyte fusion regulates cardiac development in zebrafish
Cell fusion regulates several physiological events, for example, fusion of myoblasts in skeletal muscle formation, but it is unclear if this process occurs in the heart. Here, the authors use transgenic reporters in zebrafish to show transient cardiomyocyte fusion, modulating cardiac development and function.
- Suphansa Sawamiphak
- , Zacharias Kontarakis
- & Didier Y. R. Stainier
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Article
| Open AccessEpithelial tension in the second heart field promotes mouse heart tube elongation
Epithelial progenitor cell growth in the second heart field contributes to heart morphogenesis but how this is regulated at the tissue level is unclear. Here, the authors show that cell elongation, polarized actomyosin and nuclear YAP/TAZ drive epithelial growth and correlate with mechanical tension.
- Alexandre Francou
- , Christopher De Bono
- & Robert G. Kelly
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Article
| Open AccessSfrp5 identifies murine cardiac progenitors for all myocardial structures except for the right ventricle
It is unclear which progenitors define different regions of the heart. Here, the authors find Secreted frizzled-related protein 5 is expressed in murine progenitor cells for the outflow tract, first heart field, and sinus venosus, but not the right ventricle, and Wnt inhibition prevents progenitor proliferation.
- Masayuki Fujii
- , Akane Sakaguchi
- & Hiroki Kokubo
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| Open AccessAmotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth
Growth of the mammalian heart is controlled by Hippo signalling but how this is regulated is unclear. Here, the authors show that Fat4 (an atypical cadherin) acts upstream of Hippo signalling and Fat4 mutant mice have thicker myocardium, which is mediated by the scaffold Amot1 and transcription factor Yap1.
- Chiara V. Ragni
- , Nicolas Diguet
- & Sigolène M Meilhac
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| Open AccessA strategy to discover new organizers identifies a putative heart organizer
Organizers are regions in the embryo that induce cell fate and impart pattern on neighbouring regions. Here, the authors search for new organizers based on a common gene signature, and show that the Anterior Intestinal Portal endoderm induces cardiac identity, specifies ventricle and inhibits atrial character.
- Claire Anderson
- , Mohsin A. F. Khan
- & Claudio D. Stern
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Article
| Open AccessDNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy
5-hydroxymethylation of cysteine (5-hmC) plays a role in epigenetic regulation. Here the authors analyse the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes and show that the dynamic modulation of hydroxymethylated DNA is important for cardiomyocyte gene expression programming in heart development and failure.
- Carolina M. Greco
- , Paolo Kunderfranco
- & Gianluigi Condorelli
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| Open AccessResident c-kit+ cells in the heart are not cardiac stem cells
The issue whether the cell surface protein c-kit identifies resident cardiac stem cells (CSC) is controversial. By using novel reporter mouse models, Sultana et al. show that c-kit+cells represent a subpopulation of endothelial cells in the developing and adult heart and do not exhibit CSC traits in health or disease.
- Nishat Sultana
- , Lu Zhang
- & Chen-Leng Cai
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Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function
Mechanical and electrical activity in the heart is propagated through unique cardiomyocyte membrane structures, the intercalated discs (ID). Sharma et al.identify a novel ID protein, Tmem65, that controls Ca2+ signalling and electrical coupling by interacting with and functionally regulating the gap junction protein Cx43.
- Parveen Sharma
- , Cynthia Abbasi
- & Anthony O. Gramolini
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Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease
Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al.show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.
- Aibin He
- , Fei Gu
- & William T. Pu
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| Open AccessMyocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart
The secreted ligand Angiopoietin-1 is essential for embryonic blood vessel development and adult vascular homeostasis. Here the authors show, using conditional knockout mice, that myocardium-derived Angiopoietin-1 is required for the formation of coronary veins, but not arteries.
- Yoh Arita
- , Yoshikazu Nakaoka
- & Issei Komuro
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| Open AccessGATA-dependent regulatory switches establish atrioventricular canal specificity during heart development
The atrioventricular canal partitions the developing vertebrate heart. Here, the authors show that the cardiac transcription factor Gata4 together with histone modification enzymes and localized co-factors binds atrioventricular canal-specific enhancers, thereby repressing gene activity in the cardiac chambers.
- Sonia Stefanovic
- , Phil Barnett
- & Vincent M. Christoffels
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Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development
Alternative splicing is a process during gene expression that increases the diversity of proteins encoded by a single gene. Here, the authors perform RNA-sequencing on cardiac cells from mice and show that extensive changes in gene expression and alternative splicing occur during the first month after birth.
- Jimena Giudice
- , Zheng Xia
- & Thomas A. Cooper
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Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish
T-box transcription factors such as Tbx5 have essential roles during cardiac development. Here the authors show that a member of the potassium channel tetramerization domain-containing family, Kctd10 is required for zebrafish heart development and represses the transcriptional activity of Tbx5.
- Xiangjun Tong
- , Yao Zu
- & Bo Zhang
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A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality
Nodal signalling has been implicated in the asymmetric positioning of various organs. Here, Noël et al.show that the asymmetry of the embryonic zebrafish heart is also established in the absence of Nodal signalling, suggesting a Nodal-independent mechanism that relies on actomyosin activity.
- Emily S. Noël
- , Manon Verhoeven
- & Jeroen Bakkers
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Haemogenic endocardium contributes to transient definitive haematopoiesis
Cardiac and endocardial/endothelial cells arise from progenitor cells expressing multiple haematopoietic transcription factors. Nakano and colleagues find that Nkx2–5-positive endocardial cells serve as a de novosource for definitive haematopoietic progenitors during mammalian embryogenesis.
- Haruko Nakano
- , Xiaoqian Liu
- & Atsushi Nakano
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Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling
Endothelin-1 regulates cardiovascular development by acting on neural crest cells. Here endothelin-1-deficient mice are studied, revealing that preotic neural crest cells differentiate into coronary artery smooth muscle cells through endothelin-1-dependent mechanisms.
- Yuichiro Arima
- , Sachiko Miyagawa-Tomita
- & Hiroki Kurihara
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| Open AccessChromatin remodelling complex dosage modulates transcription factor function in heart development
Inherited congenital heart defects are prevalent in the human population, but the molecular mechanisms are poorly understood. In this article, deficiency in the chromatin remodelling factor, Brg1, is shown to alter cardiac development in both mouse and zebrafish laboratory models.
- Jun K. Takeuchi
- , Xin Lou
- & Benoit G. Bruneau