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

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          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 “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 human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.

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          Most cited references19

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          Smooth muscle cell phenotypic switching in atherosclerosis.

          Smooth muscle cells (SMCs) possess remarkable phenotypic plasticity that allows rapid adaptation to fluctuating environmental cues, including during development and progression of vascular diseases such as atherosclerosis. Although much is known regarding factors and mechanisms that control SMC phenotypic plasticity in cultured cells, our knowledge of the mechanisms controlling SMC phenotypic switching in vivo is far from complete. Indeed, the lack of definitive SMC lineage-tracing studies in the context of atherosclerosis, and difficulties in identifying phenotypically modulated SMCs within lesions that have down-regulated typical SMC marker genes, and/or activated expression of markers of alternative cell types including macrophages, raise major questions regarding the contributions of SMCs at all stages of atherogenesis. The goal of this review is to rigorously evaluate the current state of our knowledge regarding possible phenotypes exhibited by SMCs within atherosclerotic lesions and the factors and mechanisms that may control these phenotypic transitions.
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            Variation in transcription factor binding among humans.

            Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee by using chromatin immunoprecipitation followed by sequencing. The binding sites of RNA polymerase II (PolII) and a key regulator of immune responses, nuclear factor kappaB (p65), were mapped in 10 lymphoblastoid cell lines, and 25 and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with single-nucleotide polymorphisms and genomic structural variants, and these differences were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between humans and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding, and they provide insight into the genetic events responsible for these differences.
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              The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors.

              The basic helix-loop-helix (bHLH) family of transcription factors orchestrates cell-fate specification, commitment and differentiation in multiple cell lineages during development. Here, we describe the role of a bHLH transcription factor, Tcf21 (epicardin/Pod1/capsulin), in specification of the cardiac fibroblast lineage. In the developing heart, the epicardium constitutes the primary source of progenitor cells that form two cell lineages: coronary vascular smooth muscle cells (cVSMCs) and cardiac fibroblasts. Currently, there is a debate regarding whether the specification of these lineages occurs early in the formation of the epicardium or later after the cells have entered the myocardium. Lineage tracing using a tamoxifen-inducible Cre expressed from the Tcf21 locus demonstrated that the majority of Tcf21-expressing epicardial cells are committed to the cardiac fibroblast lineage prior to initiation of epicardial epithelial-to-mesenchymal transition (EMT). Furthermore, Tcf21 null hearts fail to form cardiac fibroblasts, and lineage tracing of the null cells showed their inability to undergo EMT. This is the first report of a transcription factor essential for the development of cardiac fibroblasts. We demonstrate a unique role for Tcf21 in multipotent epicardial progenitors, prior to the process of EMT that is essential for cardiac fibroblast development.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                7 June 2019
                29 July 2019
                August 2019
                05 June 2020
                : 25
                : 8
                : 1280-1289
                Affiliations
                [1 ]Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, California
                [2 ]Stanford Functional Genomics Facility, Stanford University, Stanford, California
                [3 ]Stanford Cardiovascular Institute, Stanford, California
                [4 ]Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
                [5 ]Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California
                [6 ]Dept. of Genetics, Stanford University School of Medicine, Stanford, California
                [7 ]Department of Neurology and Center for Innovation in Brain Sciences, University of Arizona, Tucson, Arizona
                [8 ]Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii
                [9 ]Equal contribution
                Author notes
                [* ] Materials and Correspondence Thomas Quertermous, 300 Pasteur Dr., Falk CVRC, Stanford, CA 94305, tomq1@ 123456stanford.edu , Tel: 650-723-5012, Fax: 650-725-2178

                AUTHOR CONTRIBUTIONS

                R.C.W. designed and performed all scRNAseq experiments, analyzed the scRNAseq data, performed the RNAscope in-situ hybridization assays, performed and analyzed the CITE-seq and FACS experiments, analyzed the immunofluorescence data, performed the eQTL analyses, assisted with mouse colony breeding, drafted the manuscript, and led the study. D.W. assisted with the design of the scRNAseq experiments and performed scRNAseq capture and library preparation for all samples. D.T.P. performed scRNAseq capture and helped obtain human coronary samples. J.C. assisted with the scRNAseq capture, library preparation and sequencing. T.N. performed qPCR experiments, analyzed the qPCR data and performed TCF21 ChIPseq. M.P., C.L.M., B.L. and S.B.M. performed the eQTL analyses. R.K. performed the immunohistochemistry experiments and bred the mouse colonies. M.N. performed and analyzed immunohistochemistry experiments. K.Z., M.A. and R.C. assisted with network analysis. T.K.K., R.F. and Y.J.W. prepared the human tissue samples. M.D.T. and J.C.W. provided critical expert guidance on the manuscript. J.B.K. helped plan the mouse in situ histology studies, managed the mouse colonies, performed the TCF21 over-expression experiment and performed the quantitative immunohistochemistry analysis of lesion characteristics. T.Q. conceived and supervised the study. All authors discussed the results and contributed critical review to the manuscript.

                Article
                NIHMS1531197
                10.1038/s41591-019-0512-5
                7274198
                31359001
                091dddb3-6ba8-4797-beff-f1e749bc6109

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