Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction

Sources of Funding, see page 1845 BACKGROUND: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function.

[1]  N. Kaminski,et al.  Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis , 2020, Nature Communications.

[2]  Fabian J Theis,et al.  Generalizing RNA velocity to transient cell states through dynamical modeling , 2019, Nature Biotechnology.

[3]  R. Geffers,et al.  Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation. , 2019, JCI insight.

[4]  Ruili Huang,et al.  The NCATS BioPlanet – An Integrated Platform for Exploring the Universe of Cellular Signaling Pathways for Toxicology, Systems Biology, and Chemical Genomics , 2019, Front. Pharmacol..

[5]  Richard P Harvey,et al.  Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury , 2019, eLife.

[6]  H. Clevers,et al.  Profiling proliferative cells and their progeny in damaged murine hearts , 2018, Proceedings of the National Academy of Sciences.

[7]  E. Hirsch,et al.  Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis , 2018, Nature Communications.

[8]  Christoph Hafemeister,et al.  Comprehensive integration of single cell data , 2018, bioRxiv.

[9]  Lucas E. Wange,et al.  Sensitive and powerful single-cell RNA sequencing using mcSCRB-seq , 2018, Nature Communications.

[10]  Gordon K Smyth,et al.  The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads , 2018, bioRxiv.

[11]  Erik Sundström,et al.  RNA velocity of single cells , 2018, Nature.

[12]  A. van Oudenaarden,et al.  Single-Cell Sequencing of the Healthy and Diseased Heart Reveals Cytoskeleton-Associated Protein 4 as a New Modulator of Fibroblasts Activation , 2018, Circulation.

[13]  J. Butler,et al.  Myocardial Interstitial Fibrosis in Heart Failure: Biological and Translational Perspectives. , 2018, Journal of the American College of Cardiology.

[14]  J. Molkentin,et al.  Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart , 2018, The Journal of clinical investigation.

[15]  Paul Hoffman,et al.  Integrating single-cell transcriptomic data across different conditions, technologies, and species , 2018, Nature Biotechnology.

[16]  D. Burkhoff,et al.  Reverse remodelling and myocardial recovery in heart failure , 2018, Nature Reviews Cardiology.

[17]  Daniel A. Skelly,et al.  Single-Cell Transcriptional Profiling Reveals Cellular Diversity and Intercommunication in the Mouse Heart. , 2018, Cell reports.

[18]  J. Ruijter,et al.  Amplification of nonspecific products in quantitative polymerase chain reactions (qPCR) , 2017, Biomolecular detection and quantification.

[19]  Dae‐Ghon Kim,et al.  CTHRC1 activates pro-tumorigenic signaling pathways in hepatocellular carcinoma , 2017, Oncotarget.

[20]  Hyojin Kim,et al.  TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions , 2017, Nucleic Acids Res..

[21]  A. van Oudenaarden,et al.  Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury , 2017, Circulation.

[22]  J. Molkentin,et al.  Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. , 2017, The Journal of clinical investigation.

[23]  K. Otsu,et al.  Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis , 2017, Circulation.

[24]  Benjamin D. Greenbaum,et al.  Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses , 2017, Cell.

[25]  J. Molkentin,et al.  Redefining the identity of cardiac fibroblasts , 2017, Nature Reviews Cardiology.

[26]  N. Frangogiannis,et al.  Mechanisms of Fibroblast Activation in the Remodeling Myocardium , 2017, Current Pathobiology Reports.

[27]  P. Schultz,et al.  Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis , 2017, Proceedings of the National Academy of Sciences.

[28]  N. Hacohen,et al.  Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors , 2017, Science.

[29]  R. Baron,et al.  Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1. , 2017, Bone.

[30]  Wentian Li,et al.  Application of t-SNE to Human Genetic Data , 2017, bioRxiv.

[31]  A. Binks,et al.  Cthrc1 lowers pulmonary collagen associated with bleomycin‐induced fibrosis and protects lung function , 2017, Physiological reports.

[32]  J. Ruijter,et al.  Reference genes for gene expression studies in the mouse heart , 2017, Scientific Reports.

[33]  Malina J. Ivey,et al.  Defining the Cardiac Fibroblast. , 2016, Circulation journal : official journal of the Japanese Circulation Society.

[34]  Congxin Huang,et al.  Activin A stimulates the proliferation and differentiation of cardiac fibroblasts via the ERK1/2 and p38-MAPK pathways. , 2016, European journal of pharmacology.

[35]  Luca Scrucca,et al.  mclust 5: Clustering, Classification and Density Estimation Using Gaussian Finite Mixture Models , 2016, R J..

[36]  Howard Y. Chang,et al.  Lineage-specific and single cell chromatin accessibility charts human hematopoiesis and leukemia evolution , 2016, Nature Genetics.

[37]  B. Aronow,et al.  Genetic lineage tracing defines myofibroblast origin and function in the injured heart , 2016, Nature Communications.

[38]  Andrew D. Rouillard,et al.  The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins , 2016, Database J. Biol. Databases Curation.

[39]  M. Looso,et al.  Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. , 2016, Circulation research.

[40]  Andrew D. Rouillard,et al.  Enrichr: a comprehensive gene set enrichment analysis web server 2016 update , 2016, Nucleic Acids Res..

[41]  Andrew W. Trafford,et al.  Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling , 2016, Journal of molecular and cellular cardiology.

[42]  N. Rosenthal,et al.  Revisiting Cardiac Cellular Composition. , 2016, Circulation research.

[43]  Livia Perfetto,et al.  SIGNOR: a database of causal relationships between biological entities , 2015, Nucleic Acids Res..

[44]  N. Frangogiannis.  Pathophysiology of Myocardial Infarction. , 2015, Comprehensive Physiology.

[45]  L. Liaw,et al.  Cthrc1 controls adipose tissue formation, body composition, and physical activity , 2015, Obesity.

[46]  J. Ruijter,et al.  Removal of between-run variation in a multi-plate qPCR experiment , 2015, Biomolecular detection and quantification.

[47]  Qing-Yu He,et al.  ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization , 2015, Bioinform..

[48]  F. Prósper,et al.  Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar. , 2015, Journal of the American College of Cardiology.

[49]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[50]  K. Chan,et al.  RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation , 2014, Proceedings of the National Academy of Sciences.

[51]  J. O’Shea,et al.  Faculty Opinions recommendation of Immunogenetics. Chromatin state dynamics during blood formation. , 2014 .

[52]  D. Brenner,et al.  Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. , 2014, The Journal of clinical investigation.

[53]  G. Gabbiani.  Faculty Opinions recommendation of Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart. , 2014 .

[54]  I. Amit,et al.  Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types , 2014, Science.

[55]  Henning Hermjakob,et al.  The Reactome pathway knowledgebase , 2013, Nucleic Acids Res..

[56]  Howard Y. Chang,et al.  Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position , 2013, Nature Methods.

[57]  G. Díaz-Araya,et al.  TGF-β1 prevents simulated ischemia/reperfusion-induced cardiac fibroblast apoptosis by activation of both canonical and non-canonical signaling pathways. , 2013, Biochimica et biophysica acta.

[58]  L. Liaw,et al.  Cthrc1, a Novel Circulating Hormone Regulating Metabolism , 2012, PloS one.

[59]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[60]  N. Frangogiannis,et al.  Transforming growth factor (TGF)-β signaling in cardiac remodeling. , 2011, Journal of molecular and cellular cardiology.

[61]  J. Gardner,et al.  Induction of cardiac fibroblast lysyl oxidase by TGF-β1 requires PI3K/Akt, Smad3, and MAPK signaling. , 2011, Cytokine.

[62]  Jicheng Li,et al.  Collagen triple helix repeat containing‐1 inhibits transforming growth factor‐β1‐induced collagen type I expression in keloid , 2011, The British journal of dermatology.

[63]  N. Leslie,et al.  Migration Stimulating Factor (MSF) promotes fibroblast migration by inhibiting AKT. , 2010, Cellular signalling.

[64]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[65]  Davis J. McCarthy,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[66]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[67]  A. Moorman,et al.  Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data , 2009, Nucleic acids research.

[68]  E. Andreu,et al.  Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation. , 2008, Leukemia research.

[69]  K. Chatila,et al.  CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response1 , 2008, The Journal of Immunology.

[70]  Guofeng Ren,et al.  Essential Role of Smad3 in Infarct Healing and in the Pathogenesis of Cardiac Remodeling , 2007, Circulation.

[71]  G. Dorn,et al.  Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular Remodeling , 2007, Circulation research.

[72]  José A Ferreira,et al.  The International Journal of Biostatistics The Benjamini-Hochberg Method in the Case of Discrete Test Statistics , 2011 .

[73]  T. Durmuş,et al.  Cthrc1 Is a Novel Inhibitor of Transforming Growth Factor-&bgr; Signaling and Neointimal Lesion Formation , 2007, Circulation research.

[74]  M. Entman,et al.  Critical Role of Endogenous Thrombospondin-1 in Preventing Expansion of Healing Myocardial Infarcts , 2005, Circulation.

[75]  Steffen Jung,et al.  A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration , 2005, Nature Methods.

[76]  L. Liaw,et al.  Collagen Triple Helix Repeat Containing 1, a Novel Secreted Protein in Injured and Diseased Arteries, Inhibits Collagen Expression and Promotes Cell Migration , 2005, Circulation research.

[77]  G. Laurent,et al.  Differential roles of extracellular signal-regulated kinase 1/2 and p38MAPK in mechanical load-induced procollagen alpha1(I) gene expression in cardiac fibroblasts. , 2004, Cardiovascular research.

[78]  D. Brenner,et al.  DNase I–hypersensitive sites enhance α1(I) collagen gene expression in hepatic stellate cells , 2003 .

[79]  Pengcheng Jiang,et al.  CTHRC1 as a novel biomarker in the diagnosis of cervical squamous cell carcinoma. , 2018, International journal of clinical and experimental pathology.

[80]  M. Tallquist,et al.  Resident fibroblast expansion during cardiac growth and remodeling. , 2018, Journal of molecular and cellular cardiology.

[81]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[82]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[83]  BMC Molecular Biology BioMed Central Methodology article , 2006 .

[84]  Cathy H. Wu,et al.  UniProt: the Universal Protein knowledgebase , 2004, Nucleic Acids Res..

[85]  H. Döring.  The isolated perfused heart according to Langendorff technique--function--application. , 1990, Physiologia Bohemoslovaca.