Perpendicular alignment of lymphatic endothelial cells in response to spatial gradients in wall shear stress

Michalaki, Eleftheria; Surya, Vinay N.; Fuller, Gerald G.; Dunn, Alexander R.

doi:10.1038/s42003-019-0732-8

Cited by 30 publications

(25 citation statements)

References 53 publications

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“…The simultaneous effect of shear-cytokine activation had a strong effect on IL-6 secretion, higher than only cytokine (TNF-α/IL-1β) activation observed for low shear stress. These findings are consistent with other reports 36 – 38 . Our results verify that along the shunts proximal hole (hole located furthest from the tip) with the highest shear stress, astrocytes are significantly activated to secrete IL-6.…”

Section: Discussionsupporting

confidence: 94%

A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure

2021

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It has been hypothesized that physiological shear forces acting on medical devices implanted in the brain significantly accelerate the rate to device failure in patients with chronically indwelling neuroprosthetics. In hydrocephalus shunt devices, shear forces arise from cerebrospinal fluid flow. The shunt’s unacceptably high failure rate is mostly due to obstruction with adherent inflammatory cells. Astrocytes are the dominant cell type bound directly to obstructing shunts, rapidly manipulating their activation via shear stress-dependent cytokine secretion. Here we developed a total internal reflection fluorescence microscopy combined with a microfluidic shear device chip (MSDC) for quantitative analysis and direct spatial-temporal mapping of secreted cytokines at the single-cell level under physiological shear stress to identify the root cause for shunt failure. Real-time secretion imaging at 1-min time intervals enabled successful detection of a significant increase of astrocyte IL-6 cytokine secretion under shear stress greater than 0.5 dyne/cm2, validating our hypothesis and highlighting the importance of reducing shear stress activation of cells.

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Section: Discussionsupporting

confidence: 94%

A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure

2021

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“…In embryonic stem cell–derived ECs in vitro, Efnb2 is upregulated by shear stress, which may contribute to the stimulation of VV leaflet growth postnatally ( 12 , 63 ). This notion is consistent with the role of the oscillatory shear stress/Gata2/Foxc2 axis in LV endothelial differentiation, and the potential role of wall shear stress gradients in demarcating the locations of valve formation upstream of tributaries ( 64 – 66 ). Deletion of the mechanosensory ion channel Piezo1 results in defective VVs on P3, again consistent with a role for fluid shear in patterning VV (in addition to LV) formation ( 57 , 67 ).…”

Section: Discussionsupporting

confidence: 84%

Mutations in EPHB4 cause human venous valve aplasia

Lyons¹,

Walker²,

Seet³

et al. 2021

JCI Insight

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Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex 'organization' of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter, in mice, to study expression of its ligand, ephrinB2, and analysed developmental phenotypes following conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells, and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization, and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

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“…The higher CX43 expression under flow conditions could be related to cellular changes in response to increased WSS. [ 59,60 ] Remarkably, and consistent with previous findings, [ 61–63 ] ECs in perfused PA constructs oriented themselves perpendicular to flow, particularly in the zones #1 and 4 where maximum WSS were developed (Figure 5C,E). The orthogonal EC alignment in perfused samples suggested the formation of self‐assembled microvasculature or neovasculature, sprouting out of the bioprinted channel toward the 3D gelMA.…”

Section: Discussionsupporting

confidence: 90%

A 3D Bioprinted In Vitro Model of Pulmonary Artery Atresia to Evaluate Endothelial Cell Response to Microenvironment

Tomov

Perez

Ning

et al. 2021

Adv Healthcare Materials

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Vascular atresia are often treated via transcatheter recanalization or surgical vascular anastomosis due to congenital malformations or coronary occlusions. The cellular response to vascular anastomosis or recanalization is, however, largely unknown and current techniques rely on restoration rather than optimization of flow into the atretic arteries. An improved understanding of cellular response post anastomosis may result in reduced restenosis. Here, an in vitro platform is used to model anastomosis in pulmonary arteries (PAs) and for procedural planning to reduce vascular restenosis. Bifurcated PAs are bioprinted within 3D hydrogel constructs to simulate a reestablished intervascular connection. The PA models are seeded with human endothelial cells and perfused at physiological flow rate to form endothelium. Particle image velocimetry and computational fluid dynamics modeling show close agreement in quantifying flow velocity and wall shear stress within the bioprinted arteries. These data are used to identify regions with greatest levels of shear stress alterations, prone to stenosis. Vascular geometry and flow hemodynamics significantly affect endothelial cell viability, proliferation, alignment, microcapillary formation, and metabolic bioprofiles. These integrated in vitro-in silico methods establish a unique platform to study complex cardiovascular diseases and can lead to direct clinical improvements in surgical planning for diseases of disturbed flow.

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Perpendicular alignment of lymphatic endothelial cells in response to spatial gradients in wall shear stress

Cited by 30 publications

References 53 publications

A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure

A high-resolution real-time quantification of astrocyte cytokine secretion under shear stress for investigating hydrocephalus shunt failure

Mutations in EPHB4 cause human venous valve aplasia

A 3D Bioprinted In Vitro Model of Pulmonary Artery Atresia to Evaluate Endothelial Cell Response to Microenvironment

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