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Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis

In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) ri... Full description

Journal Title: Nature medicine 2019, Vol.25 (8), p.1280-1289
Main Author: Wirka, Robert C
Other Authors: Wagh, Dhananjay , Paik, David T , Pjanic, Milos , Nguyen, Trieu , Miller, Clint L , Kundu, Ramen , Nagao, Manabu , Coller, John , Koyano, Tiffany K , Fong, Robyn , Woo, Y Joseph , Liu, Boxiang , Montgomery, Stephen B , Wu, Joseph C , Zhu, Kuixi , Chang, Rui , Alamprese, Melissa , Tallquist, Michelle D , Kim, Juyong B , Quertermous, Thomas
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/31359001
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title: Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis
format: Article
creator:
  • Wirka, Robert C
  • Wagh, Dhananjay
  • Paik, David T
  • Pjanic, Milos
  • Nguyen, Trieu
  • Miller, Clint L
  • Kundu, Ramen
  • Nagao, Manabu
  • Coller, John
  • Koyano, Tiffany K
  • Fong, Robyn
  • Woo, Y Joseph
  • Liu, Boxiang
  • Montgomery, Stephen B
  • Wu, Joseph C
  • Zhu, Kuixi
  • Chang, Rui
  • Alamprese, Melissa
  • Tallquist, Michelle D
  • Kim, Juyong B
  • Quertermous, Thomas
subjects:
  • Animals
  • Arteries
  • Arteriosclerosis
  • Atherosclerosis
  • Basic Helix-Loop-Helix Transcription Factors - genetics
  • Basic Helix-Loop-Helix Transcription Factors - physiology
  • Cad gene
  • Cardiovascular disease
  • Care and treatment
  • Cell differentiation
  • Cell migration
  • Cells, Cultured
  • Coronary artery
  • Coronary artery disease
  • Coronary Artery Disease - prevention & control
  • Coronary heart disease
  • Gene sequencing
  • Genetic aspects
  • Genotype & phenotype
  • Health aspects
  • Health risks
  • Heart diseases
  • Humans
  • Lesions
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Modulation
  • Muscles
  • Myocytes, Smooth Muscle - physiology
  • Osteoprotegerin - genetics
  • Phenotype
  • Phenotypes
  • Polymorphism, Single Nucleotide
  • Ribonucleic acid
  • Risk factors
  • RNA
  • RNA sequencing
  • Sequence Analysis, RNA
  • Single-Cell Analysis - methods
  • Smooth muscle
  • Usage
ispartof: Nature medicine, 2019, Vol.25 (8), p.1280-1289
description: In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleAtheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis
creatorWirka, Robert C ; Wagh, Dhananjay ; Paik, David T ; Pjanic, Milos ; Nguyen, Trieu ; Miller, Clint L ; Kundu, Ramen ; Nagao, Manabu ; Coller, John ; Koyano, Tiffany K ; Fong, Robyn ; Woo, Y Joseph ; Liu, Boxiang ; Montgomery, Stephen B ; Wu, Joseph C ; Zhu, Kuixi ; Chang, Rui ; Alamprese, Melissa ; Tallquist, Michelle D ; Kim, Juyong B ; Quertermous, Thomas
creatorcontribWirka, Robert C ; Wagh, Dhananjay ; Paik, David T ; Pjanic, Milos ; Nguyen, Trieu ; Miller, Clint L ; Kundu, Ramen ; Nagao, Manabu ; Coller, John ; Koyano, Tiffany K ; Fong, Robyn ; Woo, Y Joseph ; Liu, Boxiang ; Montgomery, Stephen B ; Wu, Joseph C ; Zhu, Kuixi ; Chang, Rui ; Alamprese, Melissa ; Tallquist, Michelle D ; Kim, Juyong B ; Quertermous, Thomas
descriptionIn response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.
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languageeng
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subjectAnimals ; Arteries ; Arteriosclerosis ; Atherosclerosis ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Basic Helix-Loop-Helix Transcription Factors - physiology ; Cad gene ; Cardiovascular disease ; Care and treatment ; Cell differentiation ; Cell migration ; Cells, Cultured ; Coronary artery ; Coronary artery disease ; Coronary Artery Disease - prevention & control ; Coronary heart disease ; Gene sequencing ; Genetic aspects ; Genotype & phenotype ; Health aspects ; Health risks ; Heart diseases ; Humans ; Lesions ; Macrophages ; Mice ; Mice, Inbred C57BL ; Modulation ; Muscles ; Myocytes, Smooth Muscle - physiology ; Osteoprotegerin - genetics ; Phenotype ; Phenotypes ; Polymorphism, Single Nucleotide ; Ribonucleic acid ; Risk factors ; RNA ; RNA sequencing ; Sequence Analysis, RNA ; Single-Cell Analysis - methods ; Smooth muscle ; Usage
ispartofNature medicine, 2019, Vol.25 (8), p.1280-1289
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descriptionIn response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.
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titleAtheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis
authorWirka, Robert C ; Wagh, Dhananjay ; Paik, David T ; Pjanic, Milos ; Nguyen, Trieu ; Miller, Clint L ; Kundu, Ramen ; Nagao, Manabu ; Coller, John ; Koyano, Tiffany K ; Fong, Robyn ; Woo, Y Joseph ; Liu, Boxiang ; Montgomery, Stephen B ; Wu, Joseph C ; Zhu, Kuixi ; Chang, Rui ; Alamprese, Melissa ; Tallquist, Michelle D ; Kim, Juyong B ; Quertermous, Thomas
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abstractIn response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.
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