scholarly journals Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling

PLoS Biology ◽  
2022 ◽  
Vol 20 (1) ◽  
pp. e3001505
Author(s):  
Renee Wei-Yan Chow ◽  
Hajime Fukui ◽  
Wei Xuan Chan ◽  
Kok Soon Justin Tan ◽  
Stéphane Roth ◽  
...  
Keyword(s):  
Heart Valve ◽  
Heart Function ◽  
Molecular Signature ◽  
Mechanical Forces ◽  
Cardiovascular Development ◽  
Mechanical Stimuli ◽  
Atrioventricular Canal ◽  
Mesenchymal Transition ◽  
Valve Development

In the clinic, most cases of congenital heart valve defects are thought to arise through errors that occur after the endothelial–mesenchymal transition (EndoMT) stage of valve development. Although mechanical forces caused by heartbeat are essential modulators of cardiovascular development, their role in these later developmental events is poorly understood. To address this question, we used the zebrafish superior atrioventricular valve (AV) as a model. We found that cellularized cushions of the superior atrioventricular canal (AVC) morph into valve leaflets via mesenchymal–endothelial transition (MEndoT) and tissue sheet delamination. Defects in delamination result in thickened, hyperplastic valves, and reduced heart function. Mechanical, chemical, and genetic perturbation of cardiac forces showed that mechanical stimuli are important regulators of valve delamination. Mechanistically, we show that forces modulate Nfatc activity to control delamination. Together, our results establish the cellular and molecular signature of cardiac valve delamination in vivo and demonstrate the continuous regulatory role of mechanical forces and blood flow during valve formation.

scholarly journals Mechanically activated piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Anne-Laure Duchemin ◽  
Hélène Vignes ◽  
Julien Vermot
Keyword(s):  
Notch Signaling ◽  
Heart Valve ◽  
Notch Signaling Pathway ◽  
Outflow Tract ◽  
Mechanical Forces ◽  
Valve Development ◽  
Signaling Axis ◽  
Cell Layers ◽  
Valve Formation

Mechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are important factors modulating these pathways. In addition, live reporters reveal that Piezo controls Klf2 and Notch activity in the endothelium and Yap1 localization in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

scholarly journals Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis

2019 ◽  
Author(s):  
Anne Laure Duchemin ◽  
Hélène Vignes ◽  
Julien Vermot
Keyword(s):  
Notch Signaling ◽  
Heart Valve ◽  
Notch Signaling Pathway ◽  
Outflow Tract ◽  
Mechanical Forces ◽  
Valve Development ◽  
Signaling Axis ◽  
Cell Layers ◽  
Valve Formation

AbstractMechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are essential for regulating these pathways. In addition, live reporters reveal that piezo controls Klf2 and Notch activity in the endothelium and Yap1 expression in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.

Abstract 131: C-kit+ Cells Generated From Failed Heart Do Not Improve Failed Heart Function

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Liudmila Zakharova ◽  
Hikmet Nural ◽  
James R Nimlos ◽  
Snjezana Popovic ◽  
Lorraine Feehery ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Smooth Muscle Actin ◽  
Functional Improvement ◽  
Gene Expressions ◽  
Coronary Vein ◽  
Mesenchymal Transition

A pilot clinical study using autologous c-Kit+ cells showed improvement in cardiac functions in congestive heart failure (CHF), however, it is unclear if c-Kit+ cells isolated from CHF hearts are equally as potent as cells from controls. To test the potency of CHF c-Kit+ cells, myocardial infarction (MI) was created by permanent ligation of the left anterior descending coronary artery. Six weeks after MI, animals with left ventricle end-diastolic pressure (LVEDP) ≥20 mmHg and scar size ≥30% of left ventricle (LV) were designated as CHF rats. We found that CHF atrial explants generated less c-Kit+ cells compared to shams (15.7% vs. 11% sham vs. CHF). CHF c-Kit+ cells exhibited elevated levels of epicardial to mesenchymal transition markers, including Snail (2.5 fold) and Pai1 (3 fold), while the expression level of epithelial marker, E-cadherin was 3 fold lower in CHF c-Kit+ cells. Moreover, CHF c-Kit+ cells exhibited reduced gene expressions of pluripotency markers; 2.1 fold decrease in Nanog and 4.5 fold decrease in Sox 2 compared to sham cells. To evaluate the potency of the c-Kit+ cells, 1 x 10 6 cells isolated from CHFs or shams were delivered to 3 weeks post-MI CHF hearts. Cells were pre-labeled with GFP to enable their tracing in vivo and delivered to the infarcted myocardium via left coronary vein by a retrograde coronary sinus cell infusion (RCI). RCI delivery resulted in a cell distribution of LV (30%), right atrium (30%) and right ventricle (20%), while only 10% of cells were found in a left atrium. Three weeks after cells delivery, rats transplanted with sham c-Kit+ cells showed improved LVEDP (29.4 ± 6 vs. 11.7 ± 3.5 mmHg, CHF vs. CHF+ sham c-Kit+ cells) and a rise in peak rate of pressure (dPdt max) (3988 ± 520 vs. 5333 ± 597 mmHg/s). In contrast, no functional improvement was detected in rats transplanted with CHF c-Kit+ cells. Histological analysis demonstrated that transplanted c-Kit+/GFP+ cells were mostly incorporated into blood vessels and co-localized with endothelial marker vWf, and α-smooth muscle actin. Our results showed that left coronary vein is an efficient route for c-Kit+ cell delivery and that c-Kit+ cells isolated from CHF rats are less potent when transplanted in chronic heart failure rat model compared to those isolated from control.

scholarly journals Living myocardial slices: a novel multicellular model for cardiac translational research

2019 ◽  
Vol 41 (25) ◽  
pp. 2405-2408 ◽  
Author(s):  
Filippo Perbellini ◽  
Thomas Thum
Keyword(s):  
Translational Research ◽  
Cardiac Tissue ◽  
Heart Function ◽  
Cell Types ◽  
Human Model ◽  
Mechanical Stimuli ◽  
Cardiovascular Research ◽  
Functional Changes

Abstract Heart function relies on the interplay of several specialized cell types and a precisely regulated network of chemical and mechanical stimuli. Over the last few decades, this complexity has often been undervalued and progress in translational cardiovascular research has been significantly hindered by the lack of appropriate research models. The data collected are often oversimplified and these make the translation of results from the laboratory to clinical trials challenging and occasionally misleading. Living myocardial slices are ultrathin (100–400μm) sections of living cardiac tissue that maintain the native multicellularity, architecture, and structure of the heart and can provide information at a cellular/subcellular level. They overcome most of the limitations that affect other in vitro models and they can be prepared from human specimens, proving a clinically relevant multicellular human model for translational cardiovascular research. The publication of a reproducible protocol, and the rapid progress in methodological and technological discoveries which prevent significant structural and functional changes associated with chronic in vitro culture, has overcome the last barrier for the in vitro use of this human multicellular preparations. This technology can bridge the gap between in vitro and in vivo human studies and has the potential to revolutionize translational research approaches.

scholarly journals Muscleblind-like 1 is required for normal heart valve development in vivo

2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Ryan J. Coram ◽  
Samantha J. Stillwagon ◽  
Anuradha Guggilam ◽  
Michael W. Jenkins ◽  
Maurice S. Swanson ◽  
...  
Keyword(s):  
Heart Valve ◽  
Normal Heart ◽  
Valve Development

scholarly journals The Inter-Relationship of Periostin, TGFβ, and BMP in Heart Valve Development and Valvular Heart Diseases

2011 ◽  
Vol 11 ◽  
pp. 1509-1524 ◽  
Author(s):  
Simon J. Conway ◽  
Thomas Doetschman ◽  
Mohamad Azhar
Keyword(s):  
Heart Valve ◽  
Transforming Growth Factor ◽  
Heart Diseases ◽  
Cardiovascular Development ◽  
Valve Development ◽  
Morphogenetic Protein ◽  
Valvular Heart Diseases ◽  
Valve Diseases ◽  
Relationship Of

Recent studies have suggested an important role for periostin and transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) ligands in heart valve formation and valvular heart diseases. The function of these molecules in cardiovascular development has previously been individually reviewed, but their association has not been thoroughly examined. Here, we summarize the current understanding of the association between periostin and TGFβ and BMP ligands, and discuss the implications of this association in the context of the role of these molecules in heart valve development and valvular homeostasis. Information about hierarchal connections between periostin and TGFβ and BMP ligands in valvulogenesis will increase our understanding of the pathogenesis, progression, and medical treatment of human valve diseases.

scholarly journals The Mechanobiology of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Shahrin Islam ◽  
Kristina I. Boström ◽  
Dino Di Carlo ◽  
Craig A. Simmons ◽  
Yin Tintut ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cardiovascular System ◽  
Therapeutic Interventions ◽  
Cell Phenotype ◽  
Cardiovascular Development ◽  
Mechanical Stimuli ◽  
Mesenchymal Transition ◽  
Pulsatile Pressure ◽  
Endothelial To Mesenchymal Transition

Endothelial cells (ECs) lining the cardiovascular system are subjected to a highly dynamic microenvironment resulting from pulsatile pressure and circulating blood flow. Endothelial cells are remarkably sensitive to these forces, which are transduced to activate signaling pathways to maintain endothelial homeostasis and respond to changes in the environment. Aberrations in these biomechanical stresses, however, can trigger changes in endothelial cell phenotype and function. One process involved in this cellular plasticity is endothelial-to-mesenchymal transition (EndMT). As a result of EndMT, ECs lose cell-cell adhesion, alter their cytoskeletal organization, and gain increased migratory and invasive capabilities. EndMT has long been known to occur during cardiovascular development, but there is now a growing body of evidence also implicating it in many cardiovascular diseases (CVD), often associated with alterations in the cellular mechanical environment. In this review, we highlight the emerging role of shear stress, cyclic strain, matrix stiffness, and composition associated with EndMT in CVD. We first provide an overview of EndMT and context for how ECs sense, transduce, and respond to certain mechanical stimuli. We then describe the biomechanical features of EndMT and the role of mechanically driven EndMT in CVD. Finally, we indicate areas of open investigation to further elucidate the complexity of EndMT in the cardiovascular system. Understanding the mechanistic underpinnings of the mechanobiology of EndMT in CVD can provide insight into new opportunities for identification of novel diagnostic markers and therapeutic interventions.

scholarly journals Human rare variant and zebrafish CRISPR/Cas9-mediated mutant analyses reveal novel functions for API5, HSPB7, and LMO2 in heart failure

2021 ◽  
Author(s):  
Matthew J Winter ◽  
Yosuke Ono ◽  
Jonathan S Ball ◽  
Anna Walentinsson ◽  
Erik Michaelsson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rare Variant ◽  
Drug Targets ◽  
Heart Function ◽  
Positive Control ◽  
Cardiovascular Development ◽  
Rare Variant Analysis ◽  
Drug Target Validation ◽  
And Function

The clinical heterogeneity of heart failure has challenged our understanding of the underlying genetic mechanisms of this disease. To gain further insights into this complex pathophysiology we combined human rare variant analysis and in vivo CRISPR/Cas9-mediated mutant phenotyping in zebrafish to identify and investigate the role of 3 genes. Whole-exome sequencing of patients identified API5, HSPB7, and LMO2 as causally associated with heart failure and these genes were further investigated, alongside the positive control gata5, using CRISPR/Cas9-mediated multi-locus in vivo mutation in zebrafish. Following effective somatic mutation, we observed multiple impacts on cardiovascular development and function in F0 embryos including reductions in ventricle size, pericardial oedema, and chamber malformation. In the case of lmo2, there was also a significant impact on heart function. Our analysis suggests novel functions for API5, HSPB7, and LMO2 in human cardiovascular disease and identifies them as potential drug targets. Our data also supports in vivo CRISPR/Cas9-mediated multi-locus gene mutation analysis in F0 zebrafish as a rapid and effective primary screen for assessing gene function, as part of an integrated multi-level drug target validation strategy.

Cytoskeletal Bundle Mechanics

2007 ◽  
Author(s):  
Mark Bathe ◽  
Claus Heussinger ◽  
Mireille Claessens ◽  
Andreas Bausch ◽  
Erwin Frey
Keyword(s):  
Acoustic Waves ◽  
Actin Binding ◽  
Mechanical Resistance ◽  
Mechanical Forces ◽  
Mechanical Stimuli ◽  
Filamentous Actin ◽  
Cellular Functions ◽  
Mechanochemical Transduction ◽  
Cellular Locomotion

Filamentous actin (F-actin) is a stiff biopolymer that is tightly crosslinked in vivo by actin-binding proteins (ABPs) to form stiff bundles that form major constituents of a multitude of slender cytoskeletal processes including stereocilia, filopodia, microvilli, neurosensory bristles, cytoskeletal stress fibers, and the acrosomal process of sperm cells (Fig. 1). The mechanical properties of these cytoskeletal processes play key roles in a broad range of cellular functions — the bending stiffness of stereocilia mediates the mechanochemical transduction of mechanical stimuli such as acoustic waves to detect sound, the critical buckling load of filopodia and acrosomal processes determines their ability to withstand compressive mechanical forces generated during cellular locomotion and fertilization, and the entropic stretching stiffness of cytoskeletal bundles mediates cytoskeletal mechanical resistance to cellular deformation. Thus, a detailed understanding of F-actin bundle mechanics is fundamental to gaining a mechanistic understanding of cytoskeletal function.

Identification osteogenic signaling pathways following mechanical stimulation: A systematic review

2021 ◽  
Vol 16 ◽  
Author(s):  
Hanieh Nokhbatolfoghahaei ◽  
Maryam Rezai Rad ◽  
Zahrasadat Paknejad ◽  
Abdolreza Ardeshirylajimi ◽  
Arash Khojasteh
Keyword(s):  
Signaling Pathways ◽  
Wnt Pathway ◽  
Mechanical Forces ◽  
Mechanical Stimuli ◽  
Electronic Search ◽  
Meta Analyses ◽  
Almost All ◽  
Osteogenic Signaling

Introduction: It has been shown that mechanical forces can induce or promote osteogenic differentiation as well as remodeling of the new created bone tissues. To apply this characteristic in bone tissue engineering, it is important to know which mechanical stimuli through which signaling pathway has a more significant impact on osteogenesis. Methods: In this systematic study, an electronic search was conducted using PubMed and Google Scholar databases. This study has been prepared and organized according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Included studies were first categorized according to the in vivo and in vitro studies. Results: Six types of mechanical stresses were used in these articles and the most commonly used mechanical force and cell source were tension and bone marrow-derived mesenchymal stem cells (BMMSCs), respectively. These forces were able to trigger twelve signaling pathways in which Wnt pathway was so prominent. Conclusion: 1) Although specific signaling pathways are induced through specific mechanical forces, Wnt signaling pathways are predominantly activated by almost all types of force/stimulation, 2) All signaling pathways regulate expression of RUNX2, which is known as a master regulator of osteogenesis, 3) In Tension force, the mode of force administration, i.e, continuous or non-continuous tension is more important than the percentage of elongation.

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