scholarly journals Cardiac Organoids and Gastruloids to Study Physio-Pathological Heart Development

2021 ◽  
Vol 8 (12) ◽  
pp. 178
Author(s):  
Marisa E. Jaconi ◽  
Michel Puceat
Keyword(s):  
Embryonic Development ◽  
Heart Development ◽  
Ethical Issues ◽  
Cardiac Development ◽  
In Vitro Models ◽  
Beating Heart ◽  
Human Embryos ◽  
Functional Studies ◽  
Review Reports

Ethical issues restrict research on human embryos, therefore calling for in vitro models to study human embryonic development including the formation of the first functional organ, the heart. For the last five years, two major models have been under development, namely the human gastruloids and the cardiac organoids. While the first one mainly recapitulates the gastrulation and is still limited to investigate cardiac development, the second one is becoming more and more helpful to mimic a functional beating heart. The review reports and discusses seminal works in the fields of human gastruloids and cardiac organoids. It further describes technologies which improve the formation of cardiac organoids. Finally, we propose some lines of research towards the building of beating mini-hearts in vitro for more relevant functional studies.

Abstract 052: Epicardial-derived Adrenomedullin Drives Cardiac Hyperplasia During Embryogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sarah E Wetzel-Strong ◽  
Manyu Li ◽  
Toshio Nishikimi ◽  
Kathleen M Caron
Keyword(s):  
Embryonic Development ◽  
Heart Development ◽  
Cardiac Development ◽  
Lymphatic Vessels ◽  
Heart Weight ◽  
Cardiovascular Development ◽  
Proliferating Cells ◽  
Over Expression ◽  
Knockout Animals

The multi-functional peptide adrenomedullin ( Adm = gene, AM = protein) plays important roles in embryonic development and disease. Previous studies demonstrated that Adm knockout mice die at embryonic day 13.5 with small, disorganized hearts and hypoplastic lymphatic vessels, highlighting the importance of this peptide in normal cardiovascular development. Since Adm knockout animals are embryonic lethal, our goal was to generate and characterize a novel model of Adm over-expression to study the role of Adm during development and disease processes. Through gene targeting techniques, we generated a novel mouse model of Adm over-expression, abbreviated as Adm hi/hi . When we assessed gene expression of Adm from 10 different tissues, we found Adm hi/hi mice express 3- to 15-fold more Adm than wildtype littermates. Additionally, peptide levels of AM in lung and kidney, as well as circulating plasma levels of AM were elevated 3-fold over wildtype mice, indicating a functional increase in AM. Our initial analysis revealed that adult Adm hi/hi mice have larger heart weight to body weight ratios than wildtype littermates (4.93±0.23 vs. 5.96±0.29, n = 11-12). We found that compared to wildtype, Adm hi/hi embryos have more proliferating cells during heart development (14.46±1.11 vs. 31.97±2.84, n=4), indicating that hyperplasia drives Adm hi/hi heart enlargement. By crossing the Adm hi/hi line to different tissue-specific Cre lines, we were able to excise the stabilizing bovine growth hormone 3’UTR, thereby returning Adm expression levels back to wildtype in cells with active Cre recombinase. Using this approach, we identified the epicardium as a major source of AM during cardiac development. In conclusion, we found that AM derived primarily from the epicardium drives cardiac hyperplasia during embryonic development resulting in persistent, enlarged hearts of adult Adm hi/hi mice. Since our Adm hi/hi mice recapitulate the 3-fold plasma elevation of AM observed during human disease, this mouse line will be a useful tool for studying the role of elevated AM during disease.

Computational profiling of hiPSC-derived heart organoids reveals chamber defects associated with Ebstein’s anomaly

2020 ◽  
Author(s):  
Wei Feng ◽  
Hannah Schriever ◽  
Shan Jiang ◽  
Abha Bais ◽  
Dennis Kostka ◽  
...  
Keyword(s):  
Heart Development ◽  
Cell Types ◽  
In Vitro Models ◽  
Ebstein’S Anomaly ◽  
Great Promise ◽  
Heart Cells ◽  
Ebstein's Anomaly ◽  
Disease States ◽  
Human Fetal Heart

AbstractHeart organoids have the potential to generate primary heart-like anatomical structures and hold great promise as in vitro models for cardiac disease. However, their properties have not yet been carefully studied, which hinders a wider spread application. Here we report the development of differentiation systems for ventricular and atrial heart organoids, enabling the study of heart disease with chamber defects. We show that our systems generate organoids comprising of major cardiac cell types, and we used single cell RNA sequencing together with sample multiplexing to characterize the cells we generate. To that end, we also developed a machine learning label transfer approach lever-aging cell type, chamber, and laterality annotations available for primary human fetal heart cells. We then used this model to analyze organoid cells from an isogeneic line carrying an Ebstein’s anomaly associated genetic variant, and we successfully recapitulated the disease’s atrialized ventricular defects. In summary, we have established a workflow integrating heart organoids and computational analysis to model heart development in normal and disease states.

Hosting the preimplantation embryo: potentials and limitations of different approaches for analysing embryo - endometrium interactions in cattle

2013 ◽  
Vol 25 (1) ◽  
pp. 62 ◽  
Author(s):  
Susanne E. Ulbrich ◽  
Eckhard Wolf ◽  
Stefan Bauersachs
Keyword(s):  
Embryonic Development ◽  
In Vitro Models ◽  
Sexual Cycle ◽  
Factors Affecting ◽  
Signalling Molecules ◽  
Comprehensive Information ◽  
New Findings ◽  
Suitable Environment

Ongoing detailed investigations into embryo–maternal communication before implantation reveal that during early embryonic development a plethora of events are taking place. During the sexual cycle, remodelling and differentiation processes in the endometrium are controlled by ovarian hormones, mainly progesterone, to provide a suitable environment for establishment of pregnancy. In addition, embryonic signalling molecules initiate further sequences of events; of these molecules, prostaglandins are discussed herein as specifically important. Inadequate receptivity may impede preimplantation development and implantation, leading to embryonic losses. Because there are multiple factors affecting fertility, receptivity is difficult to comprehend. This review addresses different models and methods that are currently used and discusses their respective potentials and limitations in distinguishing key messages out of molecular twitter. Transcriptome, proteome and metabolome analyses generate comprehensive information and provide starting points for hypotheses, which need to be substantiated using further confirmatory methods. Appropriate in vivo and in vitro models are needed to disentangle the effects of participating factors in the embryo–maternal dialogue and to help distinguish associations from causalities. One interesting model is the study of somatic cell nuclear transfer embryos in normal recipient heifers. A multidisciplinary approach is needed to properly assess the importance of the uterine milieu for embryonic development and to use the large number of new findings to solve long-standing issues regarding fertility.

Vinculin knockout results in heart and brain defects during embryonic development

Development ◽  
1998 ◽  
Vol 125 (2) ◽  
pp. 327-337 ◽  
Author(s):  
W. Xu ◽  
H. Baribault ◽  
E.D. Adamson
Keyword(s):  
Embryonic Development ◽  
Focal Adhesion ◽  
Heart Development ◽  
Cardiac Development ◽  
Es Cells ◽  
Embryonic Stem ◽  
Spinal Nerve ◽  
Cell Behaviors ◽  
Migration Rates ◽  
Targeting Vector

The vinculin gene codes for a cytoskeletal protein, found in focal adhesion plaques and in cell-cell adherens junctions. Vinculin was inactivated by homologous recombination using a targeting vector in embryonic stem (ES) cells. The heterozygous ES cells were introduced into mice by established procedures to produce heterozygous animals that were normal and fertile. No homozygous vinculin−/− embryos were born and analyses during the gestational period showed that the vinculin null embryos were small and abnormal from day E8 but some survived until E10. The most prominent defect was lack of midline fusion of the rostral neural tube, producing a cranial bilobular appearance and attenuation of cranial and spinal nerve development. Heart development was curtailed at E9.5, with severely reduced and akinetic myocardial and endocardial structures. Mutant embryos were 30–40% smaller, somites and limbs were retarded and ectodermal tissues were sparse and fragile. Fibroblasts (MEF) isolated from mutant embryos were shown to have reduced adhesion to fibronectin, vitronectin, laminin and collagen compared to wild-type levels. In addition, migration rates over these substrata were two-fold higher and the level of focal adhesion kinase (FAK) activity was three-fold higher. We conclude that vinculin is necessary for normal embryonic development, probably because of its role in the regulation of cell adhesion and locomotion, cell behaviors essential for normal embryonic morphogenesis, although specific roles in neural and cardiac development cannot be ruled out.

scholarly journals Bioengineering in vitro models of embryonic development

2021 ◽  
Vol 16 (5) ◽  
pp. 1104-1116
Author(s):  
Ananya Gupta ◽  
Matthias P. Lutolf ◽  
Alex J. Hughes ◽  
Katharina F. Sonnen
Keyword(s):  
Embryonic Development ◽  
In Vitro Models

scholarly journals In vitro models of the human heart

Development ◽  
2021 ◽  
Vol 148 (16) ◽  
Author(s):  
Pablo Hofbauer ◽  
Stefan M. Jahnel ◽  
Sasha Mendjan
Keyword(s):  
Heart Development ◽  
Human Heart ◽  
Three Dimensional ◽  
Cell Types ◽  
In Vitro Models ◽  
Major Bottleneck ◽  
Key Aspects ◽  
New Generation ◽  
Self Organizing

ABSTRACT Cardiac congenital disabilities are the most common organ malformations, but we still do not understand how they arise in the human embryo. Moreover, although cardiovascular disease is the most common cause of death globally, the development of new therapies is lagging compared with other fields. One major bottleneck hindering progress is the lack of self-organizing human cardiac models that recapitulate key aspects of human heart development, physiology and disease. Current in vitro cardiac three-dimensional systems are either engineered constructs or spherical aggregates of cardiomyocytes and other cell types. Although tissue engineering enables the modeling of some electro-mechanical properties, it falls short of mimicking heart development, morphogenetic defects and many clinically relevant aspects of cardiomyopathies. Here, we review different approaches and recent efforts to overcome these challenges in the field using a new generation of self-organizing embryonic and cardiac organoids.

scholarly journals Cerebral organoids: ethical issues and consciousness assessment

2018 ◽  
Vol 44 (9) ◽  
pp. 606-610 ◽  
Author(s):  
Andrea Lavazza ◽  
Marcello Massimini
Keyword(s):  
Ethical Issues ◽  
Personalised Medicine ◽  
Three Dimensional ◽  
Cell Types ◽  
Human Embryos ◽  
Specific Cell ◽  
Neural Connections ◽  
Structural And Functional Properties ◽  
Organ Specific

Organoids are three-dimensional biological structures grown in vitro from different kinds of stem cells that self-organise mimicking real organs with organ-specific cell types. Recently, researchers have managed to produce human organoids which have structural and functional properties very similar to those of different organs, such as the retina, the intestines, the kidneys, the pancreas, the liver and the inner ear. Organoids are considered a great resource for biomedical research, as they allow for a detailed study of the development and pathologies of human cells; they also make it possible to test new molecules on human tissue. Furthermore, organoids have helped research take a step forward in the field of personalised medicine and transplants. However, some ethical issues have arisen concerning the origin of the cells that are used to produce organoids (ie, human embryos) and their properties. In particular, there are new, relevant and so-far overlooked ethical questions concerning cerebral organoids. Scientists have created so-called mini-brains as developed as a few-months-old fetus, albeit smaller and with many structural and functional differences. However, cerebral organoids exhibit neural connections and electrical activity, raising the question whether they are or (which is more likely) will one day be somewhat sentient. In principle, this can be measured with some techniques that are already available (the Perturbational Complexity Index, a metric that is directly inspired by the main postulate of the Integrated Information Theory of consciousness), which are used for brain-injured non-communicating patients. If brain organoids were to show a glimpse of sensibility, an ethical discussion on their use in clinical research and practice would be necessary.

scholarly journals Building and Repairing the Heart: What Can We Learn from Embryonic Development?

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Ana G. Freire ◽  
Tatiana P. Resende ◽  
Perpétua Pinto-do-Ó
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Embryonic Stem ◽  
Cardiac Pathophysiology ◽  
Distinct Cell ◽  
Cell Sources ◽  
Cardiac Lineage ◽  
Heart Formation ◽  
Tissue Recovery

Mammalian heart formation is a complex morphogenetic event that depends on the correct temporal and spatial contribution of distinct cell sources. During cardiac formation, cellular specification, differentiation, and rearrangement are tightly regulated by an intricate signaling network. Over the last years, many aspects of this network have been uncovered not only due to advances in cardiac development comprehension but also due to the use of embryonic stem cells (ESCs)in vitromodel system. Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease. Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration. In this review, we provide a comparative synopsis of the major signaling pathways required for cardiac lineage commitment in the embryo and murine ESCs. The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.

scholarly journals miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations

2020 ◽  
Vol 21 (3) ◽  
pp. 1158 ◽  
Author(s):  
Sarah C. Hoelscher ◽  
Theresia Stich ◽  
Anne Diehm ◽  
Harald Lahm ◽  
Martina Dreßen ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Heart Development ◽  
Regulatory Networks ◽  
Progenitor Cell ◽  
Cardiac Development ◽  
Loss Of Function ◽  
And Function ◽  
Cardiac Transcription Factors ◽  
Beating Frequency

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2+, Myh6+, Shox2+) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.

scholarly journals Muscularization of the Mesenchymal Outlet Septum during Cardiac Development

2020 ◽  
Vol 7 (4) ◽  
pp. 51
Author(s):  
Maurice J. B. van den Hoff ◽  
Andy Wessels
Keyword(s):  
Cell Polarity ◽  
Essential Role ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
In Vitro Models ◽  
Outflow Tract ◽  
Heart Tube ◽  
Tgfβ Signaling ◽  
Experimental Approaches

After the formation of the linear heart tube, it becomes divided into right and left components by the process of septation. Relatively late during this process, within the developing outflow tract, the initially mesenchymal outlet septum becomes muscularized as the result of myocardialization. Myocardialization is defined as the process in which existing cardiomyocytes migrate into flanking mesenchyme. Studies using genetically modified mice, as well as experimental approaches using in vitro models, demonstrate that Wnt and TGFβ signaling play an essential role in the regulation of myocardialization. They also show the significance of the interaction between cardiomyocytes, endocardial derived cells, neural crest cells, and the extracellular matrix. Interestingly, Wnt-mediated non-canonical planar cell polarity signaling was found to be a crucial regulator of myocardialization in the outlet septum and Wnt-mediated canonical β-catenin signaling is an essential regulator of the expansion of mesenchymal cells populating the outflow tract cushions.

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