Single-Cell Analysis Uncovers Osteoblast Factor Growth Differentiation Factor 10 as Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation Associated with Plaque Rupture in Human Carotid Artery Disease.
Karim J BrandtFabienne BurgerDaniela BaptistaAline RothRafaela Fernandes da SilvaFabrizio MontecuccoFrancois MachKapka MitevaPublished in: International journal of molecular sciences (2022)
(1) Background: Vascular smooth muscle cells (VSMCs) undergo a complex phenotypic switch in response to atherosclerosis environmental triggers, contributing to atherosclerosis disease progression. However, the complex heterogeneity of VSMCs and how VSMC dedifferentiation affects human carotid artery disease (CAD) risk has not been clearly established. (2) Method: A single-cell RNA sequencing analysis of CD45 - cells derived from the atherosclerotic aorta of Apolipoprotein E-deficient (Apoe -/- ) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the site-specific predisposition to atherosclerosis was performed. Growth Differentiation Factor 10 (GDF10) role in VSMCs phenotypic switch was investigated via flow cytometry, immunofluorescence in human atherosclerotic plaques. (3) Results: scRNAseq analysis revealed the transcriptomic profile of seven clusters, five of which showed disease-relevant gene signature of VSMC macrophagic calcific phenotype, VSMC mesenchymal chondrogenic phenotype, VSMC inflammatory and fibro-phenotype and VSMC inflammatory phenotype. Osteoblast factor GDF10 involved in ossification and osteoblast differentiation emerged as a hallmark of VSMCs undergoing phenotypic switch. Under hypercholesteremia, GDF10 triggered VSMC osteogenic switch in vitro. The abundance of GDF10 expressing osteogenic-like VSMCs cells was linked to the occurrence of carotid artery disease (CAD) events. (4) Conclusions: Taken together, these results provide evidence about GDF10-mediated VSMC osteogenic switch, with a likely detrimental role in atherosclerotic plaque stability.
Keyphrases
- single cell
- vascular smooth muscle cells
- rna seq
- endothelial cells
- mesenchymal stem cells
- coronary artery disease
- bone marrow
- angiotensin ii
- smooth muscle
- induced apoptosis
- high throughput
- flow cytometry
- induced pluripotent stem cells
- pluripotent stem cells
- cardiovascular disease
- physical activity
- stem cells
- weight loss
- oxidative stress
- risk assessment
- metabolic syndrome
- copy number
- adipose tissue
- type diabetes
- skeletal muscle
- transcription factor
- endoplasmic reticulum stress
- pulmonary arterial hypertension
- low density lipoprotein
- insulin resistance
- cell proliferation
- atomic force microscopy