@article{9e1168a98fcd4d06a6ae2647b1e966c3,
title = "Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis",
abstract = "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 {\textquoteleft}fibromyocytes{\textquoteright}, 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.",
author = "Wirka, {Robert C.} and Dhananjay Wagh and Paik, {David T.} and Milos Pjanic and Trieu Nguyen and Miller, {Clint L.} and Ramen Kundu and Manabu Nagao and John Coller and Koyano, {Tiffany K.} and Robyn Fong and Woo, {Y. Joseph} and Boxiang Liu and Montgomery, {Stephen B.} and Wu, {Joseph C.} and Kuixi Zhu and Rui Chang and Melissa Alamprese and Tallquist, {Michelle D.} and Kim, {Juyong B.} and Thomas Quertermous",
note = "Funding Information: The authors are grateful to G. Owens for providing TgMyh11-Cre, ApoE−/− animals and experimental protocols. The authors are also grateful to L. Rom{\'a}n for assistance with developing the human coronary digestion protocol. This work was supported by NIH grant F32HL129670 and AHA grant 18CDA34110206 (both to R.C.W.), and NIH grants K08HL133375 (to J.B.K.), R00HL125912 (to C.L.M.), R01HL109512 (to T.Q.), R01HL134817 (to T.Q.), R33HL120757 (to T.Q.), R01DK107437 (to T.Q.), R01HL139478 (to T.Q.), 1R01HL141371 (to J.C.W.) and 17GRNT33660474 AHA (to M.D.T.). The sequencing data were generated on an Illumina HiSeq 4000 that was purchased with funds from NIH under award number S10OD018220. Cell sorting was performed on an instrument in the Shared FACS Facility obtained using NIH S10 Shared Instrument Grant S10RR025518-01. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = aug,
day = "1",
doi = "10.1038/s41591-019-0512-5",
language = "English (US)",
volume = "25",
pages = "1280--1289",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",
}