Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis

Chen, Pei-Yu; Qin, Lingfeng; Li, Guangxin; Wang, Zheng; Dahlman, James E.; Malagon-Lopez, Jose; Gujja, Sharvari; Cilfone, Nicholas A.; Kauffman, Kevin J.; Sun, Lele; Sun, Hongye; Zhang, Xinbo; Aryal, Binod; Canfrán‐Duque, Alberto; Liu, Rebecca; Kusters, Pascal; Sehgal, Alfica; Jiao, Yang; Anderson, Daniel G.; Gulcher, Jeffrey R.; Fernández‐Hernando, Carlos; Lutgens, Esther; Schwartz, Martin A.; Pober, Jordan S.; Chittenden, Thomas; Tellides, George; Simons, Michael

doi:10.1038/s42255-019-0102-3

Cited by 231 publications

(200 citation statements)

References 44 publications

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“…24,25 within the vessel wall. Importantly, elevated TGF-β1 levels and altered downstream signalling have been implicated in the etiology of atherosclerosis 26 , vessel restenosis 27 and in the development of the neointima 28 . Genome-wide association studies have also identified chromosome 14q32 as a locus for a hitherto uncharacterized gene called HHIPL1 (Hedgehog interacting protein-like 1) 29 which encodes a sequence homolog of an antagonist of hedgehog signalling that is secreted as a pro-atherogenic protein to regulate lesion formation 30 .…”

Section: Tgf-β1 Is Released By Both Inflammatory Cells and Vascular Cmentioning

confidence: 99%

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

Molony

King

Luca

et al. 2020

Preprint

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Background: A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening, lipid retention and plaque formation, yet their origin remains controversial. The ability to discriminate heterogeneous populations of cells in the context of various disease processes is of potential clinical and diagnostic value. Methods:The feasibility of multivariate analysis of single cell photonics as a discriminator of cell phenotype was assessed using label-free optical multi-parameter interrogation of single cells on a novel Lab-on-a-Disk (LoaD) platform before myogenic differentiation of a series of multipotent stem cells in vitro, and the cellular heterogeneity within vascular lesions in vivo, was determined using supervised machine learning and validated by genetic lineage tracing in vivo.Findings: Single cell photonics were of sufficient coverage, specificity, and quality to discriminate various disparate cell phenotypes in vitro and normal medial SMCs from SMClike cells following injury ex vivo, in addition to distinguishing myogenic differentiation of a series of multipotent stem cells in vitro. Supervised machine learning of these photonic datasets supported genetic lineage tracing analysis and identified the presence of S100β + stem-derived myogenic progeny within vascular lesions, in part, due to upregulation of Coll 3A1 and elastin.Interpretation: Disease-relevant photonic signatures reflect cell type and differentiation state and may have important predictive value as a phenotypic discriminator for vascular disease. Research in contextEvidence before this study: Cardiovascular disease (CVD), the leading cause of death and disability world-wide is characterized by pathological structural changes to the blood vessel wall. Pathologic observations in humans vessels confirm that early 'transitional' lesions enriched with SMC-like cells are routinely present in atherosclerotic-prone regions of arteries during pathologic intimal thickening, prior to lipid retention, and the appearance of a atherosclerotic plaque. Lineage tracing and single cell RNA sequence analysis (scRNA-seq) analysis has provided compelling evidence for the involvement of differentiated medial SMC and adventitial/medial progenitors derived from SMCs in progressing intimal thickening.Despite these insights, the putative role of resident vascular stem cells that do not originate from medial SMCs in promoting intimal thickening remains controversial. Light as a diagnostic and prognostic tool has several advantages including high sensitivity, non-destructive measurement, small or even non-invasive analysis and low limits of detection for early detection of disease phenotypes. In combination with microfluidics, photonics enables real time measurement of single cells in very small sample volumes. To accompany these photonic platforms, deep learning, a subset of supervised machine learning based primarily on artificial neural network geometries, has rapidly grown as a predictive method t...

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Section: Tgf-β1 Is Released By Both Inflammatory Cells and Vascular Cmentioning

confidence: 99%

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

Molony

King

Luca

et al. 2020

Preprint

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“…Then, we explored why material topography mediated the adhesion of monocytes to ECs. As it was demonstrated that both ICAM-1 and VCAM-1 were closely related to the interplay of ECs and monocytes, 34,35 the endothelial expression of ICAM-1 and VCAM-1 was tested in ECs cultured on PDMS substrates with different dimensions. The gene expression of ICAM-1 and VCAM-1 was performed by RT-qPCR.…”

Section: The Adhesion Of Monocytes To Huvecs Is Affected By Wrinkledmentioning

confidence: 99%

Biointerface topography mediates the interplay between endothelial cells and monocytes

et al. 2020

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“…Recruitment of lentiviral transduced leukocytes in the sterile peritonitis model. In many murine disease models recruitment of leukocyte subpopulations of interest to the site of inflammation is a critical readout [21][22][23] . Therefore, we induced a sterile peritonitis 24 weeks following HSC transfer.…”

Section: Functional Assessment Of the Bicistronic Lentiviral Construcmentioning

confidence: 99%

A novel approach to genetic engineering of T-cell subsets by hematopoietic stem cell infection with a bicistronic lentivirus

Bogert

Furkel

Din

et al. 2020

Sci Rep

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Here we introduce a novel lentiviral construct utilizing a bicistronic lentiviral vector harboring two promoters: a global promoter (mPGK) for the expression of the selection marker (mCherry) and a second T-cell specific promoter (either dLck or CD3δ) expressing eGFP to track T-cell subsets. A dual promoter expression cassette with a cell specific second promoter permits definitive lineage specific transgenesis to investigate mechanistic and biological relevance of hematopoietic subsets in inflammatory disease models. Material and methods Lentiviral construct. Designed bicistronic lentiviral vectors harbor two constructs driven by two independent promoters. A schematic overview of the two used lentiviral vectors is presented in Fig. 1A. mPGK was used in both constructs as a global promoter located towards the 3′ end and expressing mCherry, which allows identification of successfully transduced cells. Since the global promoter is active in every cell-progenitor, T-cells and non-T-cells-successfully transduced HSCs and all their descendent daughter cells will be mCherry positive, which will allow their enrichment with fluorescence activated cell sorting (FACS) based techniques. The second T-cell specific promoter is located towards the 5′ end and was either the CMV enhanced distal Lckpromoter (dLck; 9892 bp) 8 or the CD3δ-promoter (9218 bp) 9 each controlling eGFP expression. Therefore, only committed cells with activity of the T-cell specific promoter will turn green, while non-T-cells and progenitor cells will be eGFP negative.

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Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis

Cited by 231 publications

References 44 publications

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

Disease-relevant single cell photonic signatures identify S100β stem cells and their myogenic progeny in vascular lesions

Biointerface topography mediates the interplay between endothelial cells and monocytes

A novel approach to genetic engineering of T-cell subsets by hematopoietic stem cell infection with a bicistronic lentivirus

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