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

• Published in: Nature medicine Vol. 25; no. 8; pp. 1280 - 1289
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2019; Nature Publishing Group
• Subjects: 631/208/191/2018; 631/80/304; 692/699/75/593/2100; Animals; Arteries; Arteriosclerosis; Atherosclerosis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - physiology; Biomedical and Life Sciences; Biomedicine; Cad gene; Cancer Research; Cardiovascular disease; Care and treatment; Cell differentiation; Cells, Cultured; Coronary artery; Coronary artery disease; Coronary Artery Disease - prevention & control; Coronary heart disease; Gene sequencing; Genetic aspects; Genotype & phenotype; Health aspects; Heart diseases; Humans; Infectious Diseases; Lesions; Macrophages; Metabolic Diseases; Mice; Mice, Inbred C57BL; Modulation; Molecular Medicine; Muscles; Myocytes, Smooth Muscle - physiology; Neurosciences; Osteoprotegerin - genetics; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; Ribonucleic acid; Risk factors; RNA; RNA sequencing; Sequence Analysis, RNA; Single-Cell Analysis - methods; Smooth muscle
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-019-0512-5

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. The human coronary artery disease gene TCF21 promotes the transformation of smooth muscle cells within atherosclerotic plaques into a newly identified population of fibroblast-like cells that contribute to plaque stability.