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.

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.

Treatment of Intrauterine Adhesions with Human Amnion Mesenchymal Stromal Cells (hAMSCs) on Promoting Endometrial Regeneration and Repair Via Notch Signaling Pathway Regulation

2020 ◽  
Author(s):  
Jie Yu ◽  
Wenwen Zhang ◽  
Jiayue Huang ◽  
Yating Gou ◽  
Congcong Sun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Intrauterine Adhesions ◽  
Epithelial Markers ◽  
Qrt Pcr ◽  
Endometrial Epithelial Cells

Abstract Background: Human amniotic mesenchymal stem cells(hAMSCs) can repair and improve the damaged endometrium which its aplastic disorder is the main reason for intrauterine adhesions(IUAs).Methods: We conducted in vivo and in vitro experiments. In vivo experiments: 45 female Sprague-Dawley(SD) rats were involved and randomized equally into Sham group, IUA group, Estradiol(E2) group, hAMSCs group, and E2 + hAMSCs group. The effect of hAMSCs and E2 only or combined was evaluated by Hematoxylin-eosin(HE) and Masson staining. The expression of epithelial markers and key proteins of Notch signaling pathway by Immunohistochemistry. In vitro experiments: Firstly, the hAMSCs cells were taken and divided into control group and induced group in which hAMSCs were differentiated into endometrial epithelial cells in induced microenvironment, and extracted their RNA respectively. The expression of epithelial markers and Notch1 messenger RNA (mRNA) was detected by Real-time quantitative polymerase chain reaction(qRT-PCR). and the changes in expression position of Notch intracellular domain(NICD) and expression amount of target gene, hairy enhancer of split 1(Hes1) were detected by Immunofluorescence. Then, Activated and inhibited the Notch signaling pathway while induction, and detected mRNA expression of hAMSCs epithelial markers by quantitative real-time polymerase chainreaction (qRT-PCR) respectively and detected hAMSCs cell cycle by flow cytometric. Results:This study showed that hAMSCs alone or combined with E2 could promote endometrial repair, and Notch signaling pathway a great role in it. And otherwise, the activation or habitation of Notch signaling pathway determines whether hAMSCs could differentiate into endometrial epithelial cells or not.Conclusion: we concluded that activate the Notch signaling pathway promote the differentiation of hAMSCs into endometrial epithelial cells, and further treat IUAs.

scholarly journals Sodium Tanshinone IIA Silate Exerts Microcirculation Protective Effects against Spinal Cord Injury In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Xing Li ◽  
Dan Luo ◽  
Yu Hou ◽  
Yonghui Hou ◽  
Shudong Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Endothelial Cells ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Tanshinone Iia ◽  
Protective Effects ◽  
Cord Injury

Spinal cord microcirculation involves functioning endothelial cells at the blood spinal cord barrier (BSCB) and maintains normal functioning of spinal cord neurons, axons, and glial cells. Protection of both the function and integrity of endothelial cells as well as the prevention of BSCB disruption may be a strong strategy for the treatment of spinal cord injury (SCI) cases. Sodium Tanshinone IIA silate (STS) is used for the treatment of coronary heart disease and improves microcirculation. Whether STS exhibits protective effects for SCI microcirculation is not yet clear. The purpose of this study is to investigate the protective effects of STS on oxygen-glucose deprivation- (OGD-) induced injury of spinal cord endothelial cells (SCMECs) in vitro and to explore effects on BSCB and neurovascular protection in vivo. SCMECs were treated with various concentrations of STS (1 μM, 3 μM, and 10 μM) for 24 h with or without OGD-induction. Cell viability, tube formation, migration, and expression of Notch signaling pathway components were evaluated. Histopathological evaluation (H&E), Nissl staining, BSCB permeability, and the expression levels of von Willebrand Factor (vWF), CD31, NeuN, and Notch signaling pathway components were analyzed. STS was found to improve SCMEC functions and reduce inflammatory mediators after OGD. STS also relieved histopathological damage, increased zonula occludens-1 (ZO-1), inhibited BSCB permeability, rescued microvessels, protected motor neuromas, and improved functional recovery in a SCI model. Moreover, we uncovered that the Notch signaling pathway plays an important role during these processes. These results indicated that STS protects microcirculation in SCI, which may be used as a therapeutic strategy for SCI in the future.

In vivo overactivation of the Notch signaling pathway in the developing cochlear epithelium

2015 ◽  
Vol 327 ◽  
pp. 209-217 ◽  
Author(s):  
Tomoko Tateya ◽  
Susumu Sakamoto ◽  
Itaru Imayoshi ◽  
Ryoichiro Kageyama
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway

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 Notch pathway activation targets AML-initiating cell homeostasis and differentiation

2013 ◽  
Vol 210 (2) ◽  
pp. 301-319 ◽  
Author(s):  
Camille Lobry ◽  
Panagiotis Ntziachristos ◽  
Delphine Ndiaye-Lobry ◽  
Philmo Oh ◽  
Luisa Cimmino ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Notch Signaling ◽  
Myeloproliferative Neoplasms ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Notch Receptor ◽  
Pathway Activation ◽  
Function Models

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.

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