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

Brandt, Karim J.; Burger, Fabienne; Baptista, Daniela; Roth, Aline; Fernandes da Silva, Rafaela; Montecucco, Fabrizio; Mach, Francois; Miteva, Kapka

doi:10.3390/ijms23031796

Open AccessArticle

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

by

Karim J. Brandt

^1,†,

Fabienne Burger

^1,†,

Daniela Baptista

¹,

Aline Roth

¹,

Rafaela Fernandes da Silva

^1,2,3

,

Fabrizio Montecucco

^4,5

,

Francois Mach

¹ and

Kapka Miteva

^1,*

¹

Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland

²

Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 6627, Brazil

³

Swiss Institute for Translational and Entrepreneurial Medicine, Freiburgstrasse 3, 3010 Bern, Switzerland

⁴

Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy

⁵

First Clinic of Internal Medicine, Department of Internal Medicine, Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy

^*

Author to whom correspondence should be addressed.

^†

Both authors contributed equally to this work.

Int. J. Mol. Sci. 2022, 23(3), 1796; https://doi.org/10.3390/ijms23031796

Submission received: 19 December 2021 / Revised: 21 January 2022 / Accepted: 26 January 2022 / Published: 4 February 2022

(This article belongs to the Section Molecular Biology)

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Abstract

(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.

Keywords: vascular smooth muscle cells; atherosclerosis; carotid artery disease

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MDPI and ACS Style

Brandt, K.J.; Burger, F.; Baptista, D.; Roth, A.; Fernandes da Silva, R.; Montecucco, F.; Mach, F.; Miteva, K. 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. Int. J. Mol. Sci. 2022, 23, 1796. https://doi.org/10.3390/ijms23031796

AMA Style

Brandt KJ, Burger F, Baptista D, Roth A, Fernandes da Silva R, Montecucco F, Mach F, Miteva K. 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. International Journal of Molecular Sciences. 2022; 23(3):1796. https://doi.org/10.3390/ijms23031796

Chicago/Turabian Style

Brandt, Karim J., Fabienne Burger, Daniela Baptista, Aline Roth, Rafaela Fernandes da Silva, Fabrizio Montecucco, Francois Mach, and Kapka Miteva. 2022. "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" International Journal of Molecular Sciences 23, no. 3: 1796. https://doi.org/10.3390/ijms23031796

APA Style

Brandt, K. J., Burger, F., Baptista, D., Roth, A., Fernandes da Silva, R., Montecucco, F., Mach, F., & Miteva, K. (2022). 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. International Journal of Molecular Sciences, 23(3), 1796. https://doi.org/10.3390/ijms23031796

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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

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