Single cell analysis of smooth muscle cell phenotypic modulation in vivo reveals a critical role for coronary disease gene TCF21 in mice and humans




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Robert C. Wirka1,3, Dhananjay Wagh2, David T. Paik1,3, Milos Pjanic1,3, Trieu Nguyen1,3, Clint L. Miller4, Ramen Kundu1,3, Manabu Nagao1,3, John Coller2, Tiffany K. Koyano5, Robyn Fong5, Y. Joseph Woo5, Boxiang Liu6, Stephen B. Montgomery6, Joseph C. Wu1,3, Kuixi Zhu7, Rui Chang7, Melissa Alamprese8, Michelle D. Tallquist9, Juyong B. Kim1,3,10, Thomas Quertermous1,3,10

1Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford Medicine; 2Stanford Functional Genomics Facility, Stanford University; 3Stanford Cardiovascular Institute; 4Center for Public Health Genomics, Dept of Public Health Sciences, Biochemistry and Genetics, & Biomedical Engineering, University of Virginia, Charlottesville, VA; 5Department of Cardiothoracic Surgery, Stanford Medicine; 6Dept. of Genetics, Stanford Medicine; 7Dept of Neurology & Center for Innovation in Brain Sciences, University of Arizona; 8Banner Behavior Health, Argosy University; 9Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu, HI; 10Senior Authors

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 are not established. Using single cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in both mouse and human arteries and found that these cells transform into unique fibroblast-like cells that we term “fibromyocytes”. SMC-specific knockout of TCF21, a causal CAD gene, markedly inhibited SMC phenotypic modulation in mice, leading to fewer fibromyocytes within the lesion and the protective fibrous cap. TCF21 expression was also strongly associated with SMC phenotypic modulation in diseased human coronaries. In human CAD-relevant tissues, TCF21 expression was associated with decreased CAD risk, establishing a protective role for both TCF21 and SMC phenotypic modulation in this disease.

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