<i>HHIPL1</i>
            , a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis

Aravani, Dimitra; Morris, George E.; Jones, Peter D.; Tattersall, Helena K.; Karamanavi, Elisavet; Kaiser, Michael; Kostogrys, Renata B.; Najafabadi, Maryam Ghaderi; Andrews, Sarah; Nath, Mintu; Ye, Shu; Stringer, Emma J.; Samani, Nilesh J.; Webb, Tom R.

doi:10.1161/circulationaha.119.041059

Cited by 27 publications

(26 citation statements)

References 51 publications

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“…Clearly, when the photonic profile of a range of cells in vitro and ex vivo were used as part of a training set by LDA, a substantial proportion of cells within lesions were classified as S100β + vSCs and their SHhderived myogenic progeny. This is not surprising as several previous studies support a role for Hh signalling in vascular lesion formation [20,22,23] where adventitial Sca1 + stem cells colocalise with SHh and its receptor, Ptch1 [48].…”

Section: Discussionsupporting

confidence: 53%

“…When the photonic profile of a range of cells in vitro and ex vivo were deployed as part of a training set using LDA, a substantial proportion of cells within ligated vessels were classified as S100β + vSCs and their SHh-derived myogenic progeny. Several previous lines of evidence point to a role for Hh signalling in vascular lesion formation 30,[75][76][77][78][79][80] . Adventitial Sca1 + stem cells that colocalise with SHh and its receptor, Ptch1 81 contribute to intimal thickening in vivo 77,82,83 .…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Transforming growth factor (TGF-β1) is a key cytokine regulating myogenic differentiation that is released by both inflammatory cells and vascular cells [endothelial (EC) and SMC] [15,16] within the vessel wall and has been implicated in the etiology of atherosclerosis [17], vessel restenosis [18] and the development of the neointima [19]. Similarly, Notch and hedgehog signalling components are secreted as pro-atherogenic stimuli to promote lesion formation [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…We and others have previously reported that Sonic Hedgehog/Gli signaling plays a key role in atherogenesis (Aravani et al, 2019;Morrow et al, 2007;Redmond et al, 2013), and in regulating proliferation and differentiation of a variety of stem cells (Milla et al, 2012;Mooney et al, 2015). To determine whether Sonic Hedgehog drives the differentiation of S100b+ stem cells to smooth muscle-like cells (i.e., myogenic differentiation) and whether EtOH treatment affects this, S100b + /SM-MHC -/CNN1cells were isolated from mouse thoracic aorta medial explants (Fig.…”

Section: Etoh Inhibits Sonic Hedgehog-induced Myogenic Differentiatiomentioning

confidence: 99%

Moderate Alcohol Consumption Targets S100β⁺ Vascular Stem Cells and Attenuates Injury‐Induced Neointimal Hyperplasia

Liu

Harman

DiLuca

et al. 2020

Alcoholism Clin & Exp Res

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Background Stem cells present in the vessel wall may be triggered in response to injurious stimuli to undergo differentiation and contribute to vascular disease development. Our aim was to determine the effect of moderate alcohol (EtOH) exposure on the expansion and differentiation of S100 calcium‐binding protein B positive (S100β+) resident vascular stem cells and their contribution to pathologic vessel remodeling in a mouse model of arteriosclerosis. Methods and Results Lineage tracing analysis of S100β+ cells was performed in male and female S100β‐eGFP/Cre/ERT2–dTomato transgenic mice treated daily with or without EtOH by oral gavage (peak BAC: 15 mM or 0.07%) following left common carotid artery ligation for 14 days. Carotid arteries (ligated or sham‐operated) were harvested for morphological analysis and confocal assessment of fluorescent‐tagged S100 β + cells in FFPE carotid cross sections. Ligation‐induced carotid remodeling was more robust in males than in females. EtOH‐gavaged mice had less adventitial thickening and markedly reduced neointimal formation compared to controls, with a more pronounced inhibitory effect in males compared to females. There was significant expansion of S100β+‐marked cells in vessels postligation, primarily in the neointimal compartment. EtOH treatment reduced the fraction of S100β+ cells in carotid cross sections, concomitant with attenuated remodeling. In vitro, EtOH attenuated Sonic Hedgehog‐stimulated myogenic differentiation (as evidenced by reduced calponin and myosin heavy chain expression) of isolated murine S100β+ vascular stem cells. Conclusions These data highlight resident vascular S100β+ stem cells as a novel target population for alcohol and suggest that regulation of these progenitors in adult arteries, particularly in males, may be an important mechanism contributing to the antiatherogenic effects of moderate alcohol consumption.

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Disease-Relevant Single Cell Photonic Signatures Identify S100β Stem Cells and their Myogenic Progeny in Vascular Lesions

Molony

King

Luca

et al. 2021

Stem Cell Rev and Rep

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A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening and lesion formation. While medial SMCs contribute to vascular lesions, the involvement of resident vascular stem cells (vSCs) remains unclear. We evaluated single cell photonics as a discriminator of cell phenotype in vitro before the presence of vSC within vascular lesions was assessed ex vivo using supervised machine learning and further validated using lineage tracing analysis. Using a novel lab-on-a-Disk(Load) platform, label-free single cell photonic emissions from normal and injured vessels ex vivo were interrogated and compared to freshly isolated aortic SMCs, cultured Movas SMCs, macrophages, B-cells, S100β+ mVSc, bone marrow derived mesenchymal stem cells (MSC) and their respective myogenic progeny across five broadband light wavelengths (λ465 - λ670 ± 20 nm). We found that profiles were of sufficient coverage, specificity, and quality to clearly distinguish medial SMCs from different vascular beds (carotid vs aorta), discriminate normal carotid medial SMCs from lesional SMC-like cells ex vivo following flow restriction, and identify SMC differentiation of a series of multipotent stem cells following treatment with transforming growth factor beta 1 (TGF- β1), the Notch ligand Jagged1, and Sonic Hedgehog using multivariate analysis, in part, due to photonic emissions from enhanced collagen III and elastin expression. Supervised machine learning supported genetic lineage tracing analysis of S100β+ vSCs and identified the presence of S100β+vSC-derived myogenic progeny within vascular lesions. We conclude disease-relevant photonic signatures may have predictive value for vascular disease. Graphical abstract

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HHIPL1 , a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis

Abstract: Supplemental Digital Content is available in the text.

Cited by 27 publications

References 51 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

Moderate Alcohol Consumption Targets S100β⁺ Vascular Stem Cells and Attenuates Injury‐Induced Neointimal Hyperplasia

Disease-Relevant Single Cell Photonic Signatures Identify S100β Stem Cells and their Myogenic Progeny in Vascular Lesions

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HHIPL1 , a Gene at the 14q32 Coronary Artery Disease Locus, Positively Regulates Hedgehog Signaling and Promotes Atherosclerosis

Abstract: Supplemental Digital Content is available in the text.

Cited by 27 publications

References 51 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

Moderate Alcohol Consumption Targets S100β+ Vascular Stem Cells and Attenuates Injury‐Induced Neointimal Hyperplasia

Disease-Relevant Single Cell Photonic Signatures Identify S100β Stem Cells and their Myogenic Progeny in Vascular Lesions

Contact Info

Product

Resources

About

Moderate Alcohol Consumption Targets S100β⁺ Vascular Stem Cells and Attenuates Injury‐Induced Neointimal Hyperplasia