scholarly journals Computational Modeling of Blood Flow Hemodynamics for Biomechanical Investigation of Cardiac Development and Disease

2021 ◽  
Vol 8 (2) ◽  
pp. 14
Author(s):  
Huseyin Enes Salman ◽  
Huseyin Cagatay Yalcin
Keyword(s):  
Heart Valves ◽  
Developmental Stages ◽  
Cardiac Development ◽  
Morphological Changes ◽  
Heart Defects ◽  
Animal Experiments ◽  
Cfd Modeling ◽  
Cfd Models ◽  
Developing Heart

The heart is the first functional organ in a developing embryo. Cardiac development continues throughout developmental stages while the heart goes through a serious of drastic morphological changes. Previous animal experiments as well as clinical observations showed that disturbed hemodynamics interfere with the development of the heart and leads to the formation of a variety of defects in heart valves, heart chambers, and blood vessels, suggesting that hemodynamics is a governing factor for cardiogenesis, and disturbed hemodynamics is an important source of congenital heart defects. Therefore, there is an interest to image and quantify the flowing blood through a developing heart. Flow measurement in embryonic fetal heart can be performed using advanced techniques such as magnetic resonance imaging (MRI) or echocardiography. Computational fluid dynamics (CFD) modeling is another approach especially useful when the other imaging modalities are not available and in-depth flow assessment is needed. The approach is based on numerically solving relevant physical equations to approximate the flow hemodynamics and tissue behavior. This approach is becoming widely adapted to simulate cardiac flows during the embryonic development. While there are few studies for human fetal cardiac flows, many groups used zebrafish and chicken embryos as useful models for elucidating normal and diseased cardiogenesis. In this paper, we explain the major steps to generate CFD models for simulating cardiac hemodynamics in vivo and summarize the latest findings on chicken and zebrafish embryos as well as human fetal hearts.

scholarly journals Arylamine N-acetyltransferase 2 Expression in the Developing Heart

2005 ◽  
Vol 53 (5) ◽  
pp. 583-592 ◽  
Author(s):  
Larissa Wakefield ◽  
Valerie Cornish ◽  
Fiona Broackes-Carter ◽  
Edith Sim
Keyword(s):  
Cardiac Tissue ◽  
Cardiac Development ◽  
Sinus Node ◽  
Circulation Pattern ◽  
Right Atrial ◽  
Developing Heart ◽  
Right Atrial Appendage ◽  
The Right

Murine arylamine N-acetyltransferase 2 (NAT2) is expressed in the developing heart and in the neural tube at the time of closure. Classically described as a xenobiotic metabolizing enzyme, there is increasing evidence for a distinct biological role for murine NAT2. We have characterized the expression of arylamine N-acetyltransferase 2 during cardiogenesis, mapping its expression in vivo, using a lacZ insertion deletion, and also in vitro, by measuring NAT2 enzyme activity. These findings show that cardiac Nat2 expression is both temporally and spatially regulated during development. In neonatal mice, cardiac Nat2 expression is most extensive in the central fibrous body and is evident in the atrioventricular valves and the valves of the great vessels. Whereas Nat2 expression is not detected in ventricular myocardial cells, Nat2 is strongly expressed in scattered cells in the region of the sinus node, the epicardium of the right atrial appendage, and in the pulmonary artery. Expression of active NAT2 protein is maximal when the developing heart attains the adult circulation pattern and moves from metabolizing glucose to fatty acids. NAT2 acetylating activity in cardiac tissue from Nat2−/- and Nat2+/- mice indicates a lack of compensating acetylating activity either from other acetylating enzymes or by NAT2 encoded by the wild-type Nat2 allele in Nat2+/- heterozygotes. The temporal and spatial control of murine Nat2 expression points to an endogenous role distinct from xenobiotic metabolism and indicates that Nat2 expression may be useful as a marker in cardiac development.

scholarly journals Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease

2020 ◽  
Author(s):  
Yonatan Lewis-Israeli ◽  
Aaron Wasserman ◽  
Mitchell Gabalski ◽  
Kristen Ball ◽  
Brett Volmert ◽  
...  
Keyword(s):  
Self Assembly ◽  
Human Heart ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Cellular Level ◽  
Human Model ◽  
Defined Culture

Abstract Congenital heart defects (CHD) constitute the most common birth defect in humans, affecting approximately 1% of all live births. Our ability to understand how these disorders originate is hindered by our limited ability to model the complexity of the human heart in vitro. 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 a novel method to generate human heart organoids by self-assembly using pluripotent stem cells. Our method is fully defined, highly efficient, scalable, shows high reproducibility and is compatible with screening and high-throughput approaches. Human heart organoids (hHOs) are generated using a two-step canonical Wnt signaling modulation strategy using a combination of chemical inhibitors and growth factors in completely defined culture conditions. hHOs faithfully recapitulate human cardiac development and are similar to age-matched fetal cardiac tissues at the transcriptomic, structural and cellular level. hHOs develop sophisticated internal chambers with well-organized multi-lineage cell-type regional identities reminiscent of the heart fields and the atrial and ventricular chambers, as well as the epicardium, endocardium, and coronary vasculature, and exhibit functional activity. We also show that hHOs can recreate complex metabolic disorders associated with CHD by establishing the first in vitro human model of diabetes during pregnancy (DDP) to study embryonic CHD. morphological and metabolically effects of increased glucose and insulin, showing the capability of modeling the effects of diabetes during pregnancy (DDP). Our heart organoid model constitutes a powerful novel tool for translational studies in human cardiac development and disease.

scholarly journals Evaluation of endogenous miRNA reference genes across different zebrafish strains, developmental stages and kidney disease models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Florian Siegerist ◽  
Tim Lange ◽  
Anna Iervolino ◽  
Thor Magnus Koppe ◽  
Weibin Zhou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Reference Genes ◽  
Developmental Stages ◽  
Kidney Diseases ◽  
Morphological Changes ◽  
Group Differences ◽  
Disease Models ◽  
Endogenous Reference ◽  
Process Architecture

AbstractThe majority of kidney diseases arise from the loss of podocytes and from morphological changes of their highly complex foot process architecture, which inevitably leads to a reduced kidney filtration and total loss of kidney function. It could have been shown that microRNAs (miRs) play a pivotal role in the pathogenesis of podocyte-associated kidney diseases. Due to their fully functioning pronephric kidney, larval zebrafish have become a popular vertebrate model, to study kidney diseases in vivo. Unfortunately, there is no consensus about a proper normalization strategy of RT-qPCR-based miRNA expression data in zebrafish. In this study we analyzed 9 preselected candidates dre-miR-92a-3p, dre-miR-206-3p, dre-miR-99-1, dre-miR-92b-3p, dre-miR-363-3p, dre-let-7e, dre-miR-454a, dre-miR-30c-5p, dre-miR-126a-5p for their capability as endogenous reference genes in zebrafish experiments. Expression levels of potential candidates were measured in 3 different zebrafish strains, different developmental stages, and in different kidney disease models by RT-qPCR. Expression values were analyzed with NormFinder, BestKeeper, GeNorm, and DeltaCt and were tested for inter-group differences. All candidates show an abundant expression throughout all samples and relatively high stability. The most stable candidate without significant inter-group differences was dre-miR-92b-3p making it a suitable endogenous reference gene for RT-qPCR-based miR expression zebrafish studies.

The Role of Cardiac Fibroblasts in Extracellular Matrix-Mediated Signaling During Normal and Pathological Cardiac Development

2013 ◽  
Vol 135 (7) ◽  
Author(s):  
Kelly Elizabeth Sullivan ◽  
Lauren Deems Black
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Heart Defects ◽  
Critical Role ◽  
Heart Tissue ◽  
Physical And Chemical

The extracellular matrix is no longer considered a static support structure for cells but a dynamic signaling network with the power to influence cell, tissue, and whole organ physiology. In the myocardium, cardiac fibroblasts are the primary cell type responsible for the synthesis, deposition, and degradation of matrix proteins, and they therefore play a critical role in the development and maintenance of functional heart tissue. This review will summarize the extensive research conducted in vivo and in vitro, demonstrating the influence of both physical and chemical stimuli on cardiac fibroblasts and how these interactions impact both the extracellular matrix and, by extension, cardiomyocytes. This work is of considerable significance, given that cardiovascular diseases are marked by extensive remodeling of the extracellular matrix, which ultimately impairs the functional capacity of the heart. We seek to summarize the unique role of cardiac fibroblasts in normal cardiac development and the most prevalent cardiac pathologies, including congenital heart defects, hypertension, hypertrophy, and the remodeled heart following myocardial infarction. We will conclude by identifying existing holes in the research that, if answered, have the potential to dramatically improve current therapeutic strategies for the repair and regeneration of damaged myocardium via mechanotransductive signaling.

scholarly journals Mechanosensitive Pathways in Heart Development: Findings from Chick Embryo Studies

2021 ◽  
Vol 8 (4) ◽  
pp. 32
Author(s):  
Maha Alser ◽  
Samar Shurbaji ◽  
Huseyin C. Yalcin
Keyword(s):  
Chick Embryo ◽  
Heart Development ◽  
Congenital Heart ◽  
Morphological Changes ◽  
Heart Defects ◽  
Genetic Regulation ◽  
The Body ◽  
Embryonic Chick ◽  
Chemical Treatments ◽  
Developing Heart

The heart is the first organ that starts to function in a developing embryo. It continues to undergo dramatic morphological changes while pumping blood to the rest of the body. Genetic regulation of heart development is partly governed by hemodynamics. Chick embryo is a major animal model that has been used extensively in cardiogenesis research. To reveal mechanosensitive pathways, a variety of surgical interferences and chemical treatments can be applied to the chick embryo to manipulate the blood flow. Such manipulations alter expressions of mechanosensitive genes which may anticipate induction of morphological changes in the developing heart. This paper aims to present different approaches for generating clinically relevant disturbed hemodynamics conditions using this embryonic chick model and to summarize identified mechanosensitive genes using the model, providing insights into embryonic origins of congenital heart defects.

TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis

Development ◽  
1990 ◽  
Vol 108 (4) ◽  
pp. 645-656 ◽  
Author(s):  
R.J. Akhurst ◽  
S.A. Lehnert ◽  
A. Faissner ◽  
E. Duffie
Keyword(s):  
Gestational Age ◽  
Translational Control ◽  
Heart Valves ◽  
Cardiac Development ◽  
Biological Effects ◽  
Early Embryo ◽  
Tgf Beta ◽  
Protein Levels ◽  
Developing Heart ◽  
High Level

The tissue distribution of TGF beta-1 RNA was examined within whole mouse embryos from implantation to 10.5 days gestational age and, in the developing heart, up to 8 days postpartum. The earliest high level expression of TGF beta-1 RNA is at 7.0 days postcoitum (p.c.) in the cardiac mesoderm. At 8.0 days gestational age, cardiac TGF beta-1 RNA expression is limited to endocardial cells. By 9.5 days p.c., this expression pattern becomes regionalized to those cells that overlie cardiac cushion tissue. High TGF beta-1 RNA levels continue to persist in endothelial cells of the heart valves until approximately one week postpartum. The TGF beta-1 RNA distribution was compared with the extracellular distributions of polypeptides for TGF beta and J1/tenascin. As previously reported, endothelial expression of TGF beta-1 RNA is correlated with mesenchymal expression of TGF beta polypeptide, suggesting a paracrine mode of action for this growth factor in cardiac development. Minor discrepancies in the distributions of TGF beta-1 RNA and the extracellular form of the TGF beta polypeptide suggest that translational or post-translational control of protein levels occurs and/or the possibility that the antibody used may also recognise other members of the TGF beta polypeptide family. A correlation between endothelial TGF beta-1 expression and distribution of J1/tenascin in the mesenchyme gives further support to the proposition that the biological effects of TGF beta-1 may, in part, be mediated by J1/tenascin.

scholarly journals Lamin-B1 contributes to the proper timing of epicardial cell migration and function during embryonic heart development

2016 ◽  
Vol 27 (25) ◽  
pp. 3956-3963 ◽  
Author(s):  
Joseph R. Tran ◽  
Xiaobin Zheng ◽  
Yixian Zheng
Keyword(s):  
Cell Migration ◽  
Heart Development ◽  
Developmental Stages ◽  
Morphological Changes ◽  
Nuclear Shape ◽  
Epicardial Cells ◽  
Biological Phenomena ◽  
And Migration

Lamin proteins form a meshwork beneath the nuclear envelope and contribute to many different cellular processes. Mutations in lamins cause defective organogenesis in mouse models and human diseases that affect adipose tissue, brain, skeletal muscle, and the heart. In vitro cell culture studies have shown that lamins help maintain nuclear shape and facilitate cell migration. However, whether these defects contribute to improper tissue building in vivo requires further clarification. By studying the heart epicardium during embryogenesis, we show that Lb1-null epicardial cells exhibit in vivo and in vitro migratory delay. Transcriptome analyses of these cells suggest that Lb1 influences the expression of cell adhesion genes, which could affect cell migration during epicardium development. These epicardial defects are consistent with incomplete development of both vascular smooth muscle and compact myocardium at later developmental stages in Lb1-null embryos. Further, we found that Lb1-null epicardial cells have a delayed nuclear morphology change in vivo, suggesting that Lb1 facilitates morphological changes associated with migration. These findings suggest that Lb1 contributes to nuclear shape maintenance and migration of epicardial cells and highlights the use of these cells for in vitro and in vivo study of these classic cell biological phenomena.

scholarly journals Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis

2018 ◽  
Author(s):  
Yang Liu ◽  
Pengfei Lu ◽  
Yidong Wang ◽  
Bernice E. Morrow ◽  
Bin Zhou ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Developmental Stages ◽  
Cardiac Development ◽  
Heart Defects ◽  
Enrichment Analysis ◽  
Mouse Heart ◽  
Atrioventricular Canal ◽  
Developmental Abnormalities ◽  
Highly Active

AbstractCardiac looping is an early morphogenic process critical for the formation of four-chambered mammalian hearts. To study the roles of signaling pathways, transcription factors (TFs) and genetic networks in the process, we constructed gene co-expression networks and identified gene modules highly activated in individual cardiomyocytes (CMs) at multiple anatomical regions and developmental stages. Function analyses of the module genes uncovered major pathways important for spatiotemporal CM differentiation. Interestingly, about half of the pathways were highly active in cardiomyocytes at outflow tract (OFT) and atrioventricular canal (AVC), including many well-known signaling pathways for cardiac development and several newly identified ones. Most of the OFT-AVC pathways were predicted to be regulated by 6 6 transcription factors (TFs) actively expressed at the OFT-AVC locations, with the prediction supported by motif enrichment analysis of the TF targets, including 10 TFs that have not been previously associated with cardiac development, e.g.,Etv5,Rbpms,andBaz2b. Finally, our study showed that the OFT-AVC TF targets were significantly enriched with genes associated with mouse heart developmental abnormalities and human congenital heart defects.

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

2020 ◽  
Author(s):  
Yonatan Israeli ◽  
Mitchell Gabalski ◽  
Kristen Ball ◽  
Aaron Wasserman ◽  
Jinyun Zou ◽  
...  
Keyword(s):  
Time Course ◽  
Fetal Heart ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Heart Defects ◽  
Developed Countries ◽  
Cardiovascular Development ◽  
Human Fetal Heart

AbstractCardiovascular-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 US1. Congenital heart defects (CHD) affect ∼1% of all live births2, 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 protocols3,4. 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.

scholarly journals Evaluation of Noxious Effect of Environmental Contaminants Using Zebrafish Model

2020 ◽  
Vol 2 (1) ◽  
pp. 37
Keyword(s):  
Cell Death ◽  
Developmental Stages ◽  
Morphological Changes ◽  
Cell Damage ◽  
Developmental Toxicity ◽  
Environmental Pollutant ◽  
Toxicity Study ◽  
Zebrafish Embryos ◽  
Zebrafish Model

Effects of the inorganic chemicals Calcium Fluoride (CaF2) and Hexaflurosilicilic acid (H2SiF2) have been studied due to its excessive usage in drinking water plants, glass manufacturing etc. Toxicity studies on Zebrafish embryos have been carried out for CaF2 and H2SiF2 during the embryonic developmental stages to observe the changes taken place during the growth, development. These changes can be observed in cell differentiation, larval movements, delay in hatching, and by the changes in behavior. Due to the ease with the transparency of zebrafish embryos, it can be observed and manipulated. In the field of early developmental studies, these zebrafish embryos have been vital because they have faster development by which the whole organs get developed in 3 days. Thus it plays a significant role in the discovery and analysis of changes in the developmental aspects of their teratology study. Toxicity study in Adults Zebrafish can be studied through the histology analysis where the cell damage and cell death due to fluorides and acid ions which may also lead to morphological changes due to this environmental pollutant. This toxicity study can be studied based on behavioral effects, LC50 determination, and immunohistochemistry of the brain to observe the developmental neurotoxicity. This study describes the effect of the inorganic chemicals is leading to developmental toxicity, cell deformities, and cell death with the high mortality rate in the In vivo Zebrafish model.

Sign in / Sign up

Export Citation Format

Share Document