Emergence of synchronized multicellular mechanosensing from spatiotemporal integration of heterogeneous single-cell information transfer

Zamir, Amos; Li, Guanyu; Chase, Katelyn; Moskovitch, Robert; Sun, Bo; Zaritsky, Assaf

doi:10.1016/j.cels.2022.07.002

Cited by 10 publications

(12 citation statements)

References 76 publications

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“…Importantly, disruption of Ca 2+ networks was associated with reduced vasodilation, a measure relevant to cardiovascular disorders wherein reduced vasodilation is prevalent. Studies on network activity on endothelial Ca 2+ signaling including this study have used either intact vessels or cultured cells in microfluidic devices 62,64 highlighting the importance of using the 3D MPS system for tissue-level Ca 2+ analysis. There exists tremendous opportunity to understand cardiovascular diseases and relevant pathophysiology using endothelial cell Ca 2+ network analyses in MPS models.…”

Section: Discussionmentioning

confidence: 99%

“…Our decision to utilize Ca 2+ co-activity measures is a consequence of recent literature identifying endothelial heterogeneity in Ca 2+ responses resulting in clusters of cells that show increased responsiveness to Ca 2+ agonists; in addition to synchronization and network relatedness within these clusters [60][61][62][63] . Synchronized Ca 2+ responses have in fact recently been measured in HUVECs in a microfluidic device with loss of synchronization upon gap-junction inhibition 64 . Ca 2+ network level connectivity has been experimentally validated in endothelial cells isolated from diseased animals; specifically disrupted Ca 2+ networks were observed in prediabetic obesity 62 .…”

Section: Ca 2+ Signalingmentioning

confidence: 99%

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Immune Cells and Inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Rengarajan,

Goldblatt,

Beebe

et al. 2023

Preprint

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Functional assessment of endothelium serves as an important indicator of vascular health and is compromised in vascular disorders including hypertension, atherosclerosis, and preeclampsia. Endothelial dysfunction in these cases is linked to dysregulation of the immune system involving both changes to immune cells and increased secretion of inflammatory cytokines. Herein, we utilize a well-established microfluidic device to generate a 3-dimensional vascular Microphysiological System (MPS) consisting of a tubular blood vessel lined with Human Umbilical Vein Endothelial Cells (HUVECs) to evaluate endothelial function measured via endothelial permeability and Ca2+signaling. We evaluated the effect of a mixture of factors associated with inflammation and cardiovascular disease (TNFα, VEGF-A, IL-6 at 10ng/ml each) on vascular MPS and inferred that inflammatory mediators contribute to endothelial dysfunction by disrupting the endothelial barrier over a 48-hour treatment and by diminishing coordinated Ca2+activity over a 1-hour treatment.We also evaluated the effect of peripheral blood mononuclear cells (PBMCs) on endothelial permeability and Ca2+signaling in the HUVEC MPS. HUVECs were co-cultured with PBMCs either directly wherein PBMCs passed through the lumen or embedded in the supporting collagen hydrogel. We revealed that Phytohemagglutinin (PHA)-M activated PBMCs cause endothelial dysfunction in MPS both through increased permeability and decreased coordinated Ca2+activity compared to non-activated PBMCs. Our MPS has potential applications in modeling cardiovascular disorders and screening for potential treatments using measures of endothelial function.

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Section: Discussionmentioning

confidence: 99%

Section: Ca 2+ Signalingmentioning

confidence: 99%

Immune Cells and Inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Rengarajan,

Goldblatt,

Beebe

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…[60][61][62][63] Synchronized Ca 2+ responses have in fact recently been measured in HUVECs in a microfluidic device with loss of synchronization upon gap-junction inhibition. 64 Ca 2+ network level connectivity has been experimentally validated in endothelial cells isolated from diseased animals; specifically disrupted Ca 2+ networks were observed in prediabetic obesity. 62 Importantly, disruption of Ca 2+ networks was associated with reduced vasodilation, a measure relevant to cardiovascular disorders wherein reduced vasodilation is prevalent.…”

Section: Ca 2+ Signalingmentioning

confidence: 99%

“…62 Importantly, disruption of Ca 2+ networks was associated with reduced vasodilation, a measure relevant to cardiovascular disorders wherein reduced vasodilation is prevalent. Studies demonstrating network level activity on endothelial Ca 2+ signaling including this study have used either intact vessels or cultured cells in microfluidic devices 62,64 highlighting the importance of using the 3D MPS system for tissue-level Ca 2+ analysis. There exists tremendous opportunity to understand cardiovascular diseases and relevant pathophysiology using Ca 2+ network analyses in endothelial cells using MPS models.…”

Section: Ca 2+ Signalingmentioning

confidence: 99%

Immune cells and inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Rengarajan,

Goldblatt,

Beebe

et al. 2024

Lab Chip

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“…Nonetheless, the combination of single cell imaging analysis, multicellular engineered systems, and time-course perturbational experimental designs has provided insights into the mechanisms of multicellular information processing (14,77,(82)(83)(84).…”

Section: Multicellular Information Processing In Tissuesmentioning

confidence: 99%

Complementing Cell Taxonomies with a Multicellular Analysis of Tissues

Ramirez Flores,

Schäfer,

Küchenhoff

et al. 2024

Physiology

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The application of single cell molecular profiling coupled with spatial technologies has enabled charting cellular heterogeneity in reference tissues and in disease. This new wave of molecular data has highlighted the expected diversity of single cell dynamics upon shared external queues and spatial organizations. However, little is known about the relationship between single cell heterogeneity and the emergence and maintenance of robust multicellular processes in developed tissues and its role in (patho)physiology. Here, we present emerging computational modeling strategies that use increasingly available large-scale cross-condition single cell and spatial datasets, to study multicellular organization in tissues and complement cell taxonomies. This perspective should enable us to better understand how cells within tissues collectively process information and adapt synchronized responses in disease contexts and to bridge the gap between structural changes and functions in tissues.

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Emergence of synchronized multicellular mechanosensing from spatiotemporal integration of heterogeneous single-cell information transfer

Cited by 10 publications

References 76 publications

Immune Cells and Inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Immune Cells and Inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Immune cells and inflammatory mediators cause endothelial dysfunction in a vascular microphysiological system

Complementing Cell Taxonomies with a Multicellular Analysis of Tissues

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