Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta

Campinho, Pedro; Lamperti, Paola; Boselli, Francesco; Vilfan, Andrej; Vermot, Julien

doi:10.1016/j.celrep.2020.03.069

Cited by 36 publications

(31 citation statements)

References 70 publications

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“…However, our results indicate that without a strong intracellular cytoskeletal network regulated by Snai1, the heartbeat-induced mechanical forces can lead to an increase in cell extrusion. While it has been shown that an increase in cell contractility due to changes in morphology, adhesion or cell density drives cell extrusion 23,24,26,28,29,52,53 , we present evidence that external mechanical forces contribute to non-apoptotic CM extrusion during cardiac development, and that actomyosin and IF cytoskeletal regulation is critical to prevent CM extrusion.…”

Section: Desmin B Overexpression In Cms Promotes Their Extrusionmentioning

confidence: 50%

The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression

Gentile

Bensimon-Brito

Priya

et al. 2020

Preprint

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The zinc finger transcription factor Snai1 is a well-known regulator of epithelial-to-mesenchymal transition (EMT)1, 2; it is required for mesoderm ingression in flies3 and neural crest delamination in vertebrates4. During cardiac development, Snai1-regulated EMT is necessary for myocardial precursor migration and valve formation5, 6. However, a role for Snai1 in maturing cardiomyocytes (CMs) has not been reported. Here, using genetic, transcriptomic and chimeric analyses in zebrafish, we find that Snai1b is required for myocardial wall integrity. Global loss of snai1b leads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions in snai1b mutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the α-catenin epitope α-18. By comparing the transcriptome of wild-type and snai1b mutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation of desmin b. We tested the role of desmin b in myocardial wall integrity and found that CM-specific desmin b overexpression led to CM extrusion, recapitulating the snai1b mutant phenotype. Altogether, these results indicate that Snai1 is a critical regulator of intermediate filament gene expression in CMs, and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressing desmin b expression.

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Section: Desmin B Overexpression In Cms Promotes Their Extrusionmentioning

confidence: 50%

The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression

Gentile

Bensimon-Brito

Priya

et al. 2020

Preprint

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“…In addition, the contribution of different flow-derived forces (e.g., shear stress and circumferential stretch) to specific EC behaviors involved in vascular morphogenesis still needs to be clarified. These open questions are difficult and will benefit from a number of new tools: optogenetics (Chow and Vermot, 2017;Krueger et al, 2019), functionalized protein binders (Bieli et al, 2016), three dimensional live-imaging and processing (Campinho et al, 2020;Prahst et al, 2020) as well as tissue engineering approaches where forces are trackable and accurately controlled (Duchemin et al, 2019b;Vianello and Lutolf, 2019).…”

Section: Resultsmentioning

confidence: 99%

Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior

2020

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The endothelium is the cell monolayer that lines the interior of the blood vessels separating the vessel lumen where blood circulates, from the surrounding tissues. During embryonic development, endothelial cells (ECs) must ensure that a tight barrier function is maintained whilst dynamically adapting to the growing vascular tree that is being formed and remodeled. Blood circulation generates mechanical forces, such as shear stress and circumferential stretch that are directly acting on the endothelium. ECs actively respond to flow-derived mechanical cues by becoming polarized, migrating and changing neighbors, undergoing shape changes, proliferating or even leaving the tissue and changing identity. It is now accepted that coordinated changes at the single cell level drive fundamental processes governing vascular network morphogenesis such as angiogenic sprouting, network pruning, lumen formation, regulation of vessel caliber and stability or cell fate transitions. Here we summarize the cell biology and mechanics of ECs in response to flow-derived forces, discuss the latest advances made at the single cell level with particular emphasis on in vivo studies and highlight potential implications for vascular pathologies.

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“…It is important to note that force has also been shown to activate mechanosensitive ion channels [3,65]. In a zebrafish model analyzing the impact of blood flow on endothelial cell extrusion, the mechanosensitive cationic channel polycystic kidney disease 2 (pkd2) was found to be responsible for modulating endothelial cell extrusion independent of primary cilia [65]. This finding contrasts with other work that implicates primary cilia as mechanosensors in EHT [66].…”

mentioning

confidence: 82%

“…Cyclic strain in the hemogenic endothelium is necessary for HSPC maintenance, maturation, and proliferation via YAP1 signaling [103] 2020 Blood flow regulates endothelial cell extrusion in blood vessels [65] activation, which is important for downstream mechanotransduction signaling and cytoskeletal remodeling [51,53]. VEcadherin is a vital component of adherens junctions and plays a key role in maintaining vascular integrity [51,52,58].…”

mentioning

confidence: 99%

“…Together with PECAM-1 and VEGF-R2, VE-cadherin has been shown to activate MAPK, Akt, and PI3K signaling pathways, which have all been implicated in hematopoiesis [3,[62][63][64]. It is important to note that force has also been shown to activate mechanosensitive ion channels [3,65]. In a zebrafish model analyzing the impact of blood flow on endothelial cell extrusion, the mechanosensitive cationic channel polycystic kidney disease 2 (pkd2) was found to be responsible for modulating endothelial cell extrusion independent of primary cilia [65].…”

mentioning

confidence: 99%

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Biomechanical Regulation of Hematopoietic Stem Cells in the Developing Embryo

Horton

Dumbali

Bhanu

et al. 2021

Curr. Tissue Microenviron. Rep.

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Purpose of Review The contribution of biomechanical forces to hematopoietic stem cell (HSC) development in the embryo is a relatively nascent area of research. Herein, we address the biomechanics of the endothelial-to-hematopoietic transition (EHT), impact of force on organelles, and signaling triggered by extrinsic forces within the aorta-gonad-mesonephros (AGM), the primary site of HSC emergence. Recent Findings Hemogenic endothelial cells undergo carefully orchestrated morphological adaptations during EHT. Moreover, expansion of the stem cell pool during embryogenesis requires HSC extravasation into the circulatory system and transit to the fetal liver, which is regulated by forces generated by blood flow. Findings from other cell types also suggest that forces external to the cell are sensed by the nucleus and mitochondria. Interactions between these organelles and the actin cytoskeleton dictate processes such as cell polarization, extrusion, division, survival, and differentiation. Summary Despite challenges of measuring and modeling biophysical cues in the embryonic HSC niche, the past decade has revealed critical roles for mechanotransduction in governing HSC fate decisions. Lessons learned from the study of the embryonic hematopoietic niche promise to provide critical insights that could be leveraged for improvement in HSC generation and expansion ex vivo.

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Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta

Abstract: Highlights d Endothelial cell (EC) nuclei are enriched in the ventral dorsal aorta (DA) during EC movement d DA wall deforms asymmetrically in response to pulsatile blood flow d Low blood flow or abnormal mechanosensing results in increased cell extrusion

Cited by 36 publications

References 70 publications

The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression

The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression

Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior

Biomechanical Regulation of Hematopoietic Stem Cells in the Developing Embryo

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