Genomic, Transcriptomic, and Proteomic Depiction of Induced Pluripotent Stem Cells–Derived Smooth Muscle Cells As Emerging Cellular Models for Arterial Diseases

Liu, Lu; Jouve, Charléne; Henry, Josephine; Berrandou, Takiy-Eddine; Hulot, Jean‐Sébastien; Georges, Adrien; Bouatia-Naji, Nabila

doi:10.1161/hypertensionaha.122.19733

Cited by 7 publications

(15 citation statements)

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“…The field is advancing with novel strategies to differentiate VSMCs without having to expose cells to different growth factors that may variably influence the phenotype of VSMCs, as highlighted in the current issue. 3 Liu et al 3 implemented a protocol using the small molecule RepSox, identified as a promoter of SM-MHC positive cell differentiation via activation of NOTCH signaling, 8 as a model for development of procontractile VSMCs (R-SMCs). The authors compared this model with the classical TGF-β/PDGF model of VSMC differentiation (TP-SMCs; Figure ).…”

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confidence: 99%

“…Taken together, the work from Liu et al 3 has revealed new models to study genetic and epigenetic factors relevant to cardiovascular diseases. In addition to deeply characterizing iPSC-SMCs using different cell differentiation approaches, this study 3 further raises important questions as to why gene profiles of apparent contractile and proliferative VSMCs differ depending on the experimental strategies used to differentiate cells. Moreover, these differential findings raise concerns regarding how closely iPSC-VSMCs recapitulate apparent VSMC changes in vascular changes associated with cardiovascular disease.…”

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confidence: 97%

“…Liu et al 3 implemented a protocol using the small molecule RepSox, identified as a promoter of SM-MHC positive cell differentiation via activation of NOTCH signaling, 8 as a model for development of procontractile VSMCs (R-SMCs). The authors compared this model with the classical TGF-β/PDGF model of VSMC differentiation (TP-SMCs; Figure).…”

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confidence: 99%

“…Investigation of molecular processes underlying phenotypic switching is critical for mechanism- and disease-specific therapeutic targeting of VSMC-related cardiovascular diseases. In the present issue of Hypertension , Liu et al 3 deeply characterized 2 human induced pluripotent stem cell (iPSC)–derived smooth muscle cell (SMC) models representing quiescent/procontractile and proliferative/synthetic VSMCs and shed light on epigenetic and transcriptional properties involved in VSMC differentiation and plasticity and the implications in pathological conditions (Figure).…”

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Phenotype-Specific Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells to Model Vascular Disease: Implications of Differentiation Protocols

Camargo

Touyz

2023

Hypertension

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confidence: 99%

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Phenotype-Specific Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells to Model Vascular Disease: Implications of Differentiation Protocols

Camargo

Touyz

2023

Hypertension

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Regulatory mechanisms in multiple vascular diseases locusLRP1involve repression by SNAIL and extracellular matrix remodeling

Liu

Henry

Liu

et al. 2023

Preprint

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Background: Genome-wide association studies (GWAS) implicate common genetic variations in the low-density lipoprotein receptor-related protein 1 locus (LRP1) in risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown. Methods: Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells (iPSC) were genome-edited using CRISPR-Cas9 to delete or modify candidate enhancer regions, and generate LRP1 knockout cell lines (KO). Cells were differentiated into smooth muscle cells (SMCs) through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA-sequencing and mass spectrometry. Results: Multi-trait co-localization analyses pointed at rs11172113 as the most likely causal variant in LRP1 for fibromuscular dysplasia, migraine, pulse pressure and pulmonary function trait. We found rs11172113-T allele to associate with higher LRP1 expression. Genomic deletion in iPSC-derived SMCs supported rs11172113 to locate in an enhancer region regulating LRP1 expression. We found transcription factors MECP2 and SNAIL to repress LRP1 expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele. LRP1 KO decreased iPSC-derived SMCs proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix, connective tissue and lung development. LRP1 KO showed potentiated canonical TGFβ signaling through enhanced phosphorylation of SMAD2/3. Analyses of protein content of decellularized extracts indicated partial extracellular matrix (ECM) remodeling involving enhanced secretion of CYR61, a known LRP1 ligand involved in vascular integrity and TIMP3, implicated in extracellular matrix maintenance and also known to interact with LRP1. Conclusions: Our findings support allele specific LRP1 gene repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreased LRP1 expression in SMCs to remodel the ECM enhanced by TGFβ as a potential mechanism of this pleiotropic locus for vascular diseases.

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ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

Liu,

Esmael

et al. 2024

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IntroductionSCAD (spontaneous coronary artery dissection) is a form of myocardial infarction that disproportionately affects young women. SCAD is caused by the formation of a hematoma within coronary artery wall, resulting in its blockage. Sixteen SCAD susceptibility loci are currently known, includingZNF827gene locus on chromosome 4. Several common genetic variations withinZNF827are also linked to coronary artery disease (CAD), systolic blood pressure (SBP), and ascending aortic diameter. The molecular processes driving these genetic connections, however, are unknown.MethodsWe performed fine-mapping and genetic colocalization analysis atZNF827locus on multiple GWAS signals and quantitative expression traits. We explored the regulatory function of sequences of interest using a luciferase reporter system in rat smooth muscle cells. We used siRNA to knockdown the expression of gene and assessed transcriptomic changes through bulk RNA-Seq.ResultsThe genetic association signals for SCAD, CAD, blood pressure, and aorta dimensions could all be explained by a single causal variant. We identified rs13128814 as the most likely causative variant. This variant overlaps epigenetic regulatory markers specifically active in vascular SMCs and fibroblasts. A 1kb region containing the SCAD-risk allele (A) of rs13128814 variant had a transcriptional activation impact, while the protective allele (G) had no effect. In silico predictions found nuclear factor 1 (NF1) transcription factors preferentially bind to the A allele of rs13128814. We found that overexpressing NFIA (Nuclear Factor 1 A-Type) activated transcription in this area. SCAD association andZNF827eQTL colocalization in various vascular tissues suggested the latter as a plausible target gene in this locus. Knockdown ofZNF827in iPSC-derived SMCs and fibroblasts, followed by RNA-seq, identified a large number of dysregulated genes, including multiple genes involved in cardiovascular disease.ConclusionOur findings inZNF827locus support the hypothesis that the rs13128814 variant, which may affect the binding of NF1 family transcription factors and causeZNF827expression to be deregulated, is the molecular mechanism underpinning the relationship of theZNF827locus with numerous cardiovascular disorders.ZNF827acts as a regulator of gene expression in vascular SMCs and fibroblasts. Further investigation ofZNF827function in vascular tissue will be required to understand the implications of its dysregulation on cardiovascular physiopathology.

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Genomic, Transcriptomic, and Proteomic Depiction of Induced Pluripotent Stem Cells–Derived Smooth Muscle Cells As Emerging Cellular Models for Arterial Diseases

Cited by 7 publications

References 78 publications

Phenotype-Specific Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells to Model Vascular Disease: Implications of Differentiation Protocols

Phenotype-Specific Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells to Model Vascular Disease: Implications of Differentiation Protocols

Regulatory mechanisms in multiple vascular diseases locusLRP1involve repression by SNAIL and extracellular matrix remodeling

ZNF827pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

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