Cardiac repair by epicardial EMT: Current targets and a potential role for the primary cilium

Abba, 2016, MicroRNA regulation of epithelial to mesenchymal transition, Journal of Clinical Medicine, 5, 8, 10.3390/jcm5010008 Andrae, 2008, Role of platelet-derived growth factors in physiology and medicine, Genes & Development, 22, 1276, 10.1101/gad.1653708 Aurora, 2014, Macrophages are required for neonatal heart regeneration, The Journal of Clinical Investigation, 124, 1382, 10.1172/JCI72181 Banai, 1994, Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs, Circulation, 89, 2183, 10.1161/01.CIR.89.5.2183 Banerjee, 2012, Thymosin beta 4 is dispensable for murine cardiac development and function, Circulation Research, 110, 456, 10.1161/CIRCRESAHA.111.258616 Bao, 2016, Long-term self-renewing human epicardial cells generated from pluripotent stem cells under defined xeno-free conditions, Nature Biomedical Engineering, 1, 0003, 10.1038/s41551-016-0003 Bartram, 2001, Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-β2-knockout mice, Circulation, 103, 2745, 10.1161/01.CIR.103.22.2745 Blom, 2016, Myocardial infarction in neonatal mice, a model of cardiac regeneration, Journal of Visualized Experiments, 111 Blom, 2016, Primary cilia disassembly promotes mammalian cardiac regeneration, The FASEB Journal, 30, 1207.7 Boopathy, 2015, Intramyocardial delivery of notch ligand-containing hydrogels improves cardiac function and angiogenesis following infarction, Tissue Engineering. Part A, 21, 2315, 10.1089/ten.tea.2014.0622 Borovina, 2010, Vangl2 directs the posterior tilting and asymmetric localization of motile primary cilia, Nature Cell Biology, 12, 407, 10.1038/ncb2042 Bronnum, 2013, miR-21 promotes fibrogenic epithelial-to-mesenchymal transition of epicardial mesothelial cells involving programmed cell death 4 and Sprouty-1, PLoS One, 8, 10.1371/journal.pone.0056280 Cai, 2008, A myocardial lineage derives from Tbx18 epicardial cells, Nature, 454, 104, 10.1038/nature06969 Cao, 2010, Intraflagellar transport proteins are essential for cilia formation and for planar cell polarity, Journal of the American Society of Nephrology: JASN, 21, 1326, 10.1681/ASN.2009091001 Caspary, 2007, The graded response to sonic hedgehog depends on cilia architecture, Developmental Cell, 12, 767, 10.1016/j.devcel.2007.03.004 Cervantes, 2010, Primary cilia regulate Gli/hedgehog activation in pancreas, Proceedings of the National Academy of Sciences of the United States of America, 107, 10109, 10.1073/pnas.0909900107 Chen, 2002, Epicardial induction of fetal cardiomyocyte proliferation via a retinoic acid-inducible trophic factor, Developmental Biology, 250, 198, 10.1006/dbio.2002.0796 Chen, 2013, Stimulation of adult resident cardiac progenitor cells by durable myocardial expression of thymosin beta 4 with ultrasound-targeted microbubble delivery, Gene Therapy, 20, 225, 10.1038/gt.2012.89 Chiu, 2012, Controlled release of thymosin β4 from injected collagen-chitosan hydrogels promotes angiogenesis and prevents tissue loss after myocardial infarction, Regenerative Medicine, 7, 523, 10.2217/rme.12.35 Christensen, 2017, Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor β (TGF-β) signaling, Cold Spring Harbor Perspectives in Biology, 9, 10.1101/cshperspect.a028167 Christia, 2013, Targeting inflammatory pathways in myocardial infarction, European Journal of Clinical Investigation, 43, 986, 10.1111/eci.12118 Clement, 2013, TGF-β signaling is associated with endocytosis at the pocket region of the primary cilium, Cell Reports, 3, 1806, 10.1016/j.celrep.2013.05.020 Clement, 2009, The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation, Journal of Cell Science, 122, 3070, 10.1242/jcs.049676 Cong, 2013, Downregulated microRNA-200a promotes EMT and tumor growth through the Wnt/β-catenin pathway by targeting the E-cadherin repressors ZEB1/ZEB2 in gastric adenocarcinoma, Oncology Reports, 29, 1579, 10.3892/or.2013.2267 Corbit, 2008, Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms, Nature Cell Biology, 10, 70, 10.1038/ncb1670 Davenport, 2005, An incredible decade for the primary cilium: A look at a once-forgotten organelle, American Journal of Physiology. Renal Physiology, 289, F1159, 10.1152/ajprenal.00118.2005 David, 2012, Dishonorable discharge: The oncogenic roles of cleaved E-cadherin fragments, Cancer Research, 72, 2917, 10.1158/0008-5472.CAN-11-3498 de Vreede, 1991, Did prognosis after acute myocardial infarction change during the past 30 years? A meta-analysis, Journal of the American College of Cardiology, 18, 698, 10.1016/0735-1097(91)90792-8 Delewi, 2014, Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: A collaborative meta-analysis, European Heart Journal, 35, 989, 10.1093/eurheartj/eht372 Djebali, 2012, Landscape of transcription in human cells, Nature, 489, 101, 10.1038/nature11233 Duan, 2012, Wnt1/β-catenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair, The EMBO Journal, 31, 429, 10.1038/emboj.2011.418 Duim, 2015, Cardiac endothelial cells express Wilms' tumor-1: Wt1 expression in the developing, adult and infarcted heart, Journal of Molecular and Cellular Cardiology, 81, 127, 10.1016/j.yjmcc.2015.02.007 Egorova, 2011, Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition, Circulation Research, 108, 1093, 10.1161/CIRCRESAHA.110.231860 Encode Project Consortium, 2012, An integrated encyclopedia of DNA elements in the human genome, Nature, 489, 57, 10.1038/nature11247 Ezratty, 2011, A role for the primary cilium in notch signaling and epidermal differentiation during skin development, Cell, 145, 1129, 10.1016/j.cell.2011.05.030 Fang, 2016, Epicardium-derived fibroblasts in heart development and disease, Journal of Molecular and Cellular Cardiology, 91, 23, 10.1016/j.yjmcc.2015.12.019 Foglio, 2015, Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis, International Journal of Cardiology, 197, 333, 10.1016/j.ijcard.2015.06.008 Forsythe, 1996, Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1, Molecular and Cellular Biology, 16, 4604, 10.1128/MCB.16.9.4604 Frangogiannis, 2014, The immune system and the remodeling infarcted heart: Cell biological insights and therapeutic opportunities, Journal of Cardiovascular Pharmacology, 63, 185, 10.1097/FJC.0000000000000003 Fujita, 2005, Efficacy of photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2 in a rabbit model of chronic myocardial infarction, The Journal of Surgical Research, 126, 27, 10.1016/j.jss.2004.12.025 Gaetani, 2015, Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction, Biomaterials, 61, 339, 10.1016/j.biomaterials.2015.05.005 Gerber, 2016, Mortality associated with heart failure after myocardial infarction: A contemporary community perspective, Circulation. Heart Failure, 9, 10.1161/CIRCHEARTFAILURE.115.002460 Germani, 2015, Generation of cardiac progenitor cells through epicardial to mesenchymal transition, Journal of Molecular Medicine (Berlin, Germany), 93, 735, 10.1007/s00109-015-1290-2 Gherghiceanu, 2012, Cardiac telocytes - Their junctions and functional implications, Cell and Tissue Research, 348, 265, 10.1007/s00441-012-1333-8 Gidh-Jain, 1998, Alterations in cardiac gene expression during ventricular remodeling following experimental myocardial infarction, Journal of Molecular and Cellular Cardiology, 30, 627, 10.1006/jmcc.1997.0628 Gong, 2018, Knockdown of long non-coding RNA MEG3 protects H9c2 cells from hypoxia-induced injury by targeting microRNA-183, Journal of Cellular Biochemistry, 119, 1429, 10.1002/jcb.26304 Gonzalez-Rosa, 2012, Pan-epicardial lineage tracing reveals that epicardium derived cells give rise to myofibroblasts and perivascular cells during zebrafish heart regeneration, Developmental Biology, 370, 173, 10.1016/j.ydbio.2012.07.007 Grieskamp, 2011, Notch signaling regulates smooth muscle differentiation of epicardium-derived cells, Circulation Research, 108, 813, 10.1161/CIRCRESAHA.110.228809 Guadix, 2011, Wt1 controls retinoic acid signalling in embryonic epicardium through transcriptional activation of Raldh2, Development, 138, 1093, 10.1242/dev.044594 Guo, 2017, Regulatory non-coding RNAs in acute myocardial infarction, Journal of Cellular and Molecular Medicine, 21, 1013, 10.1111/jcmm.13032 Gutschner, 2013, MALAT1 — A paradigm for long noncoding RNA function in cancer, Journal of Molecular Medicine (Berlin, Germany), 91, 791, 10.1007/s00109-013-1028-y Hartsock, 2008, Adherens and tight junctions: Structure, function and connections to the actin cytoskeleton, Biochimica et Biophysica Acta, 1778, 660, 10.1016/j.bbamem.2007.07.012 Hassounah, 2012, Molecular pathways: The role of primary cilia in cancer progression and therapeutics with a focus on hedgehog signaling, Clinical Cancer Research, 18, 2429, 10.1158/1078-0432.CCR-11-0755 Haubner, 2012, Complete cardiac regeneration in a mouse model of myocardial infarction, Aging (Albany NY), 4, 966, 10.18632/aging.100526 Hayashi, 2015, The spectrum of epidemiology underlying sudden cardiac death, Circulation Research, 116, 1887, 10.1161/CIRCRESAHA.116.304521 Haycraft, 2005, Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function, PLoS Genetics, 1, 10.1371/journal.pgen.0010053 Heery, 2017, Long non-coding RNAs: Key regulators of epithelial-mesenchymal transition, tumour drug resistance and cancer stem cells, Cancer, 9, 38, 10.3390/cancers9040038 Hesse, 2017, CD73-derived adenosine and tenascin-C control cytokine production by epicardium-derived cells formed after myocardial infarction, FASEB Journal, 31, 3040, 10.1096/fj.201601307R Huangfu, 2003, Hedgehog signalling in the mouse requires intraflagellar transport proteins, Nature, 426, 83, 10.1038/nature02061 Ibrahim, 2017, Hypoxia causes downregulation of dicer in hepatocellular carcinoma, which is required for upregulation of hypoxia-inducible factor 1α and epithelial-mesenchymal transition, Clinical Cancer Research, 1 Iyer, 2015, Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells, Development, 142, 1528, 10.1242/dev.119271 Jacoby, 2009, INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse, Nature Genetics, 41, 1027, 10.1038/ng.427 Jechlinger, 2006, Autocrine PDGFR signaling promotes mammary cancer metastasis, The Journal of Clinical Investigation, 116, 1561, 10.1172/JCI24652 Jeong, 2013, The effect of rigorous study design in the research of autologous bone marrow-derived mononuclear cell transfer in patients with acute myocardial infarction, Stem Cell Research & Therapy, 4, 82, 10.1186/scrt233 Ji, 2003, MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer, Oncogene, 22, 8031, 10.1038/sj.onc.1206928 Jing, 2016, Hypoxia induced the differentiation of Tbx18-positive epicardial cells to CoSMCs, Scientific Reports, 6 Jones, 2008, Ciliary proteins link basal body polarization to planar cell polarity regulation, Nature Genetics, 40, 69, 10.1038/ng.2007.54 Jopling, 2010, Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation, Nature, 464, 606, 10.1038/nature08899 Kikuchi, 2011, Tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration, Development, 138, 2895, 10.1242/dev.067041 Kim, 2010, PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts, Proceedings of the National Academy of Sciences of the United States of America, 107, 17206, 10.1073/pnas.0915016107 Koefoed, 2014, Cilia and coordination of signaling networks during heart development, Organogenesis, 10, 108, 10.4161/org.27483 Kong, 2009, miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells, Stem Cells, 27, 1712, 10.1002/stem.101 Korpal, 2008, The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis, RNA Biology, 5, 115, 10.4161/rna.5.3.6558 Korpal, 2008, The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2, The Journal of Biological Chemistry, 283, 14910, 10.1074/jbc.C800074200 Koudstaal, 2014, Sustained delivery of insulin-like growth factor-1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart, Journal of Cardiovascular Translational Research, 7, 232, 10.1007/s12265-013-9518-4 Kozminski, 1993, A motility in the eukaryotic flagellum unrelated to flagellar beating, Proceedings of the National Academy of Sciences of the United States of America, 90, 5519, 10.1073/pnas.90.12.5519 Kreidberg, 1993, WT-1 is required for early kidney development, Cell, 74, 679, 10.1016/0092-8674(93)90515-R Kumarswamy, 2012, MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer, International Journal of Cancer, 130, 2044, 10.1002/ijc.26218 Lamouille, 2013, Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs, Current Opinion in Cell Biology, 25, 200, 10.1016/j.ceb.2013.01.008 Lamouille, 2014, Molecular mechanisms of epithelial-mesenchymal transition, Nature Reviews. Molecular Cell Biology, 15, 178, 10.1038/nrm3758 Lancaster, 2011, Subcellular spatial regulation of canonical Wnt signalling at the primary cilium, Nature Cell Biology, 13, 700, 10.1038/ncb2259 Lechtreck, 2015, IFT-cargo interactions and protein transport in cilia, Trends in Biochemical Sciences, 40, 765, 10.1016/j.tibs.2015.09.003 Leitch, 2014, Basal body proteins regulate notch signaling through endosomal trafficking, Journal of Cell Science, 127, 2407, 10.1242/jcs.130344 Lepilina, 2006, A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration, Cell, 127, 607, 10.1016/j.cell.2006.08.052 Letterio, 1994, Maternal rescue of transforming growth factor-beta 1 null mice, Science, 264, 1936, 10.1126/science.8009224 Li, 2015, Global genetic analysis in mice unveils central role for cilia in congenital heart disease, Nature, 521, 520, 10.1038/nature14269 Limana, 2010, Myocardial infarction induces embryonic reprogramming of epicardial c-kit+ cells: Role of the pericardial fluid, Journal of Molecular and Cellular Cardiology, 48, 609, 10.1016/j.yjmcc.2009.11.008 Lin, 2003, Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease, Proceedings of the National Academy of Sciences of the United States of America, 100, 5286, 10.1073/pnas.0836980100 Liu, 2014, Effectiveness and safety of selected bone marrow stem cells on left ventricular function in patients with acute myocardial infarction: A meta-analysis of randomized controlled trials, International Journal of Cardiology, 177, 764, 10.1016/j.ijcard.2014.11.005 Liu, 2014, Epicardium-to-fat transition in injured heart, Cell Research, 24, 1367, 10.1038/cr.2014.125 Ma, 2005, PKD2 functions as an epidermal growth factor-activated plasma membrane channel, Molecular and Cellular Biology, 25, 8285, 10.1128/MCB.25.18.8285-8298.2005 Ma, 2005, Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning, Development, 132, 5601, 10.1242/dev.02156 Ma, 2010, miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis, Nature Cell Biology, 12, 247, 10.1038/ncb2024 Manner, 1999, Does the subepicardial mesenchyme contribute myocardioblasts to the myocardium of the chick embryo heart? A quail-chick chimera study tracing the fate of the epicardial primordium, The Anatomical Record, 255, 212, 10.1002/(SICI)1097-0185(19990601)255:2<212::AID-AR11>3.0.CO;2-X Mannherz, 2009, The beta-thymosins: Intracellular and extracellular activities of a versatile actin binding protein family, Cell Motility and the Cytoskeleton, 66, 839, 10.1002/cm.20371 Martinez-Estrada, 2010, Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of snail and E-cadherin, Nature Genetics, 42, 89, 10.1038/ng.494 May-Simera, 2010, Bbs8, together with the planar cell polarity protein Vangl2, is required to establish left-right asymmetry in zebrafish, Developmental Biology, 345, 215, 10.1016/j.ydbio.2010.07.013 Mellgren, 2008, Platelet-derived growth factor receptor beta signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations, Circulation Research, 103, 1393, 10.1161/CIRCRESAHA.108.176768 Mendez, 2010, Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition, The FASEB Journal, 24, 1838, 10.1096/fj.09-151639 Merki, 2005, Epicardial retinoid X receptor α is required for myocardial growth and coronary artery formation, Proceedings of the National Academy of Sciences of the United States of America, 102, 18455, 10.1073/pnas.0504343102 Mewhort, 2014, Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling, The Journal of Thoracic and Cardiovascular Surgery, 147, 1650, 10.1016/j.jtcvs.2013.08.005 Michalik, 2014, Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth, Circulation Research, 114, 1389, 10.1161/CIRCRESAHA.114.303265 Missinato, 2015, Extracellular component hyaluronic acid and its receptor Hmmr are required for epicardial EMT during heart regeneration, Cardiovascular Research, 107, 487, 10.1093/cvr/cvv190 Mitsos, 2012, Therapeutic angiogenesis for myocardial ischemia revisited: Basic biological concepts and focus on latest clinical trials, Angiogenesis, 15, 1, 10.1007/s10456-011-9240-2 Miyagawa, 2017, Phase I clinical trial of autologous stem cell-sheet transplantation therapy for treating cardiomyopathy, Journal of the American Heart Association, 6, 10.1161/JAHA.116.003918 Mondal, 2015, MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures, Nature Communications, 6, 7743, 10.1038/ncomms8743 Moore, 1999, YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis, Development, 126, 1845, 10.1242/dev.126.9.1845 Moyer, 1994, Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice, Science, 264, 1329, 10.1126/science.8191288 Murcia, 2000, The oak ridge polycystic kidney (Orpk) disease gene is required for left-right axis determination, Development, 127, 2347, 10.1242/dev.127.11.2347 Murry, 2004, Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts, Nature, 428, 664, 10.1038/nature02446 Neugebauer, 2009, FGF signalling during embryo development regulates cilia length in diverse epithelia, Nature, 458, 651, 10.1038/nature07753 Nielsen, 2015, PDGFRβ and oncogenic mutant PDGFRα D842V promote disassembly of primary cilia through a PLCγ- and AURKA-dependent mechanism, Journal of Cell Science, 128, 3543, 10.1242/jcs.173559 Oishi, 2006, Regulation of primary cilia formation and left-right patterning in zebrafish by a noncanonical Wnt signaling mediator, duboraya, Nature Genetics, 38, 1316, 10.1038/ng1892 Olson, 2009, The actin cytoskeleton in cancer cell motility, Clinical & Experimental Metastasis, 26, 273, 10.1007/s10585-008-9174-2 Paunovic, 2017, Phenotypic screen for cardiac regeneration identifies molecules with differential activity in human epicardium-derived cells versus cardiac fibroblasts, ACS Chemical Biology, 12, 132, 10.1021/acschembio.6b00683 Pazour, 2000, Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella, The Journal of Cell Biology, 151, 709, 10.1083/jcb.151.3.709 Pennisi, 2009, FGFR-1 is required by epicardium-derived cells for myocardial invasion and correct coronary vascular lineage differentiation, Developmental Biology, 328, 148, 10.1016/j.ydbio.2009.01.023 Piccoli, 2017, Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction, Circulation Research, 121, 575, 10.1161/CIRCRESAHA.117.310624 Popescu, 2010, Telocytes in human epicardium, Journal of Cellular and Molecular Medicine, 14, 2085, 10.1111/j.1582-4934.2010.01129.x Porrello, 2011, Transient regenerative potential of the neonatal mouse heart, Science, 331, 1078, 10.1126/science.1200708 Porrello, 2013, Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family, Proceedings of the National Academy of Sciences of the United States of America, 110, 187, 10.1073/pnas.1208863110 Poss, 2002, Heart regeneration in zebrafish, Science, 298, 2188, 10.1126/science.1077857 Ptaszek, 2012, Towards regenerative therapy for cardiac disease, Lancet, 379, 933, 10.1016/S0140-6736(12)60075-0 Public Health Agency of Canada, 2009, Tracking heart and stroke in Canada 2009 Ramjee, 2017, Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction, The Journal of Clinical Investigation, 127, 899, 10.1172/JCI88759 Rane, 2011, Increased infarct wall thickness by a bio-inert material is insufficient to prevent negative left ventricular remodeling after myocardial infarction, PLoS One, 6, 10.1371/journal.pone.0021571 Rao, 2015, Human epicardial cell-conditioned medium contains HGF/IgG complexes that phosphorylate RYK and protect against vascular injury, Cardiovascular Research, 107, 277, 10.1093/cvr/cvv168 Reiss, 1993, ANG II receptors, c-myc, and c-jun in myocytes after myocardial infarction and ventricular failure, The American Journal of Physiology, 264, H760 Ridley, 2011, Life at the leading edge, Cell, 145, 1012, 10.1016/j.cell.2011.06.010 Rohatgi, 2007, Patched1 regulates hedgehog signaling at the primary cilium, Science, 317, 372, 10.1126/science.1139740 Roush, 2008, The let-7 family of microRNAs, Trends in Cell Biology, 18, 505, 10.1016/j.tcb.2008.07.007 Rozycki, 2014, The fate of the primary cilium during myofibroblast transition, Molecular Biology of the Cell, 25, 643, 10.1091/mbc.e13-07-0429 Rui, 2014, Extending the time window of mammalian heart regeneration by thymosin β4, Journal of Cellular and Molecular Medicine, 18, 2417, 10.1111/jcmm.12421 Ruiz-Villalba, 2015, Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar, Journal of the American College of Cardiology, 65, 2057, 10.1016/j.jacc.2015.03.520 Russell, 2011, A dynamic notch injury response activates epicardium and contributes to fibrosis repair, Circulation Research, 108, 51, 10.1161/CIRCRESAHA.110.233262 Sadoshima, 1992, Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy, The Journal of Biological Chemistry, 267, 10551, 10.1016/S0021-9258(19)50052-7 Sanchez-Duffhues, 2015, SLUG is expressed in endothelial cells lacking primary cilia to promote cellular calcification, Arteriosclerosis, Thrombosis, and Vascular Biology, 35, 616, 10.1161/ATVBAHA.115.305268 Sasaki, 2013, The small molecule Wnt signaling modulator ICG-001 improves contractile function in chronically infarcted rat myocardium, PLoS One, 8, 10.1371/journal.pone.0075010 Schneider, 2010, Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts, Cellular Physiology and Biochemistry, 25, 279, 10.1159/000276562 Schneider, 2005, PDGFRαα signaling is regulated through the primary cilium in fibroblasts, Current Biology, 15, 1861, 10.1016/j.cub.2005.09.012 Seeger, 2016, Inhibition of let-7 augments the recruitment of epicardial cells and improves cardiac function after myocardial infarction, Journal of Molecular and Cellular Cardiology, 94, 145, 10.1016/j.yjmcc.2016.04.002 Seeley, 2009, Constructing and deconstructing roles for the primary cilium in tissue architecture and cancer, Methods in Cell Biology, 94, 299, 10.1016/S0091-679X(08)94015-2 Serpooshan, 2013, The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction, Biomaterials, 34, 9048, 10.1016/j.biomaterials.2013.08.017 Shyu, 2002, Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat, Cardiovascular Research, 54, 576, 10.1016/S0008-6363(02)00259-6 Singh, 2011, MicroRNA-processing enzyme dicer is required in epicardium for coronary vasculature development, The Journal of Biological Chemistry, 286, 41036, 10.1074/jbc.M111.268573 Smart, 2011, De novo cardiomyocytes from within the activated adult heart after injury, Nature, 474, 640, 10.1038/nature10188 Smart, 2007, Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization, Nature, 445, 177, 10.1038/nature05383 Smith, 2011, Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling, Circulation Research, 108, e15, 10.1161/CIRCRESAHA.110.235531 Stark, 2016, Systemic dosing of thymosin beta 4 before and after ischemia does not attenuate global myocardial Iischemia-reperfusion injury in pigs, Frontiers in Pharmacology, 7, 115, 10.3389/fphar.2016.00115 Statistics Canada, 2011 Su, 2013, MicroRNA-221 mediates the effects of PDGF-BB on migration, proliferation, and the epithelial-mesenchymal transition in pancreatic cancer cells, PLoS One, 8, 10.1371/journal.pone.0071309 Su, 2012, MicroRNA-200a suppresses the Wnt/β-catenin signaling pathway by interacting with β-catenin, International Journal of Oncology, 40, 1162 Sun, 2014, Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer, Tumour Biology, 35, 1065, 10.1007/s13277-013-1142-z Talman, 2016, Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration, Cell and Tissue Research, 365, 563, 10.1007/s00441-016-2431-9 Tano, 2014, Epicardial placement of mesenchymal stromal cell-sheets for the treatment of ischemic cardiomyopathy; in vivo proof-of-concept study, Molecular Therapy, 22, 1864, 10.1038/mt.2014.110 Tao, 2013, Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium, Developmental Biology, 376, 136, 10.1016/j.ydbio.2013.01.026 Tarride, 2009, A review of the cost of cardiovascular disease, The Canadian Journal of Cardiology, 25, e195, 10.1016/S0828-282X(09)70098-4 Taulman, 2001, Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia, Molecular Biology of the Cell, 12, 589, 10.1091/mbc.12.3.589 Tripathi, 2010, The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation, Molecular Cell, 39, 925, 10.1016/j.molcel.2010.08.011 Umberger, 2015, Ciliary transport regulates PDGF-AA/αα signaling via elevated mammalian target of rapamycin signaling and diminished PP2A activity, Molecular Biology of the Cell, 26, 350, 10.1091/mbc.e14-05-0952 Valenta, 2012, The many faces and functions of β-catenin, The EMBO Journal, 31, 2714, 10.1038/emboj.2012.150 van den Akker, 2005, Platelet-derived growth factors in the developing avian heart and maturating coronary vasculature, Developmental Dynamics, 233, 1579, 10.1002/dvdy.20476 van den Borne, 2010, Myocardial remodeling after infarction: The role of myofibroblasts, Nature Reviews. Cardiology, 7, 30, 10.1038/nrcardio.2009.199 Van der Heiden, 2006, Monocilia on chicken embryonic endocardium in low shear stress areas, Developmental Dynamics, 235, 19, 10.1002/dvdy.20557 van Tuyn, 2007, Epicardial cells of human adults can undergo an epithelial-to-mesenchymal transition and obtain characteristics of smooth muscle cells in vitro, Stem Cells, 25, 271, 10.1634/stemcells.2006-0366 van Wijk, 2012, Cardiac regeneration from activated epicardium, PLoS One, 7, 10.1371/journal.pone.0044692 Vicente-Steijn, 2015, Regional differences in WT-1 and Tcf21 expression during ventricular development: Implications for myocardial compaction, PLoS One, 10, 10.1371/journal.pone.0136025 Vieira, 2017, BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease, Nature Communications, 8, 10.1038/ncomms16034 von Gise, 2012, Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease, Circulation Research, 110, 1628, 10.1161/CIRCRESAHA.111.259960 Wang, 2015, Epicardial regeneration is guided by cardiac outflow tract and hedgehog signalling, Nature, 522, 226, 10.1038/nature14325 Wang, 2015, Cardiovascular risk factors and in-hospital mortality in acute coronary syndromes: Insights from the Canadian global registry of acute coronary events, The Canadian Journal of Cardiology, 31, 1455, 10.1016/j.cjca.2015.04.007 Wang, 2017, Mesenchymal stem cell-loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium, Journal of Cellular and Molecular Medicine, 21, 1751, 10.1111/jcmm.13097 Ware, 1997, Angiogenesis in ischemic heart disease, Nature Medicine, 3, 158, 10.1038/nm0297-158 Wei, 2015, Epicardial FSTL1 reconstitution regenerates the adult mammalian heart, Nature, 525, 479, 10.1038/nature15372 Winter, 2007, Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart, Circulation, 116, 917, 10.1161/CIRCULATIONAHA.106.668178 Winter, 2009, A new direction for cardiac regeneration therapy: Application of synergistically acting epicardium-derived cells and cardiomyocyte progenitor cells, Circulation. Heart Failure, 2, 643, 10.1161/CIRCHEARTFAILURE.108.843722 Witty, 2014, Generation of the epicardial lineage from human pluripotent stem cells, Nature Biotechnology, 32, 1026, 10.1038/nbt.3002 World Health Organization, 2015, 937 Wu, 2013, Tbx18 regulates development of the epicardium and coronary vessels, Developmental Biology, 383, 307, 10.1016/j.ydbio.2013.08.019 Xiang, 2016, Silencing of long non-coding RNA MALAT1 promotes apoptosis of glioma cells, Journal of Korean Medical Science, 31, 688, 10.3346/jkms.2016.31.5.688 Xiang, 2014, Cardiac-specific overexpression of human stem cell factor promotes epicardial activation and arteriogenesis after myocardial infarction, Circulation. Heart Failure, 7, 831, 10.1161/CIRCHEARTFAILURE.114.001423 Xiang, 2009, Cardiomyocyte-specific overexpression of human stem cell factor improves cardiac function and survival after myocardial infarction in mice, Circulation, 120, 1065, 10.1161/CIRCULATIONAHA.108.839068 Xiang, 2017, MALAT1 modulates TGF-beta1-induced endothelial-to-mesenchymal transition through downregulation of miR-145, Cellular Physiology and Biochemistry, 42, 357, 10.1159/000477479 Xin, 2013, Hippo pathway effector Yap promotes cardiac regeneration, Proceedings of the National Academy of Sciences of the United States of America, 110, 13839, 10.1073/pnas.1313192110 Yanagisawa-Miwa, 1992, Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor, Science, 257, 1401, 10.1126/science.1382313 Yang, 2015, Wnt signaling through Snail1 and Zeb1 regulates bone metastasis in lung cancer, American Journal of Cancer Research, 5, 748 Yang, 2016, Long non-coding RNA MALAT1 mediates transforming growth factor β1-induced epithelial-mesenchymal transition of retinal pigment epithelial cells, PLoS One, 11 Yeh, 2013, IGF-1 activates a cilium-localized noncanonical Gbetagamma signaling pathway that regulates cell-cycle progression, Developmental Cell, 26, 358, 10.1016/j.devcel.2013.07.014 Zakharova, 2012, Cardiac explant-derived cells are regulated by Notch-modulated mesenchymal transition, PLoS One, 7, 10.1371/journal.pone.0037800 Zamora, 2007, Epicardium-derived progenitor cells require beta-catenin for coronary artery formation, Proceedings of the National Academy of Sciences of the United States of America, 104, 18109, 10.1073/pnas.0702415104 Zangi, 2013, Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction, Nature Biotechnology, 31, 898, 10.1038/nbt.2682 Zangi, 2017, Insulin-like growth factor 1 receptor-dependent pathway drives epicardial adipose tissue formation after myocardial injury, Circulation, 135, 59, 10.1161/CIRCULATIONAHA.116.022064 Zhang, 1996, Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development, Development, 122, 2977, 10.1242/dev.122.10.2977 Zhang, 2017, LncRNA MEG3 inhibits cell epithelial-mesenchymal transition by sponging miR-421 targeting E-cadherin in breast cancer, Biomedicine & Pharmacotherapy, 91, 312, 10.1016/j.biopha.2017.04.085 Zhang, 2009, Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: A meta-analysis of randomised controlled trials, International Journal of Cardiology, 136, 178, 10.1016/j.ijcard.2008.04.071 Zhao, 2017, Efficient differentiation of TBX18+/WT1+ epicardial-like cells from human pluripotent stem cells using small molecular compounds, Stem Cells and Development, 26, 528, 10.1089/scd.2016.0208 Zhao, 2013, Cardiac telocytes were decreased during myocardial infarction and their therapeutic effects for ischaemic heart in rat, Journal of Cellular and Molecular Medicine, 17, 123, 10.1111/j.1582-4934.2012.01655.x Zhou, 2011, Adult mouse epicardium modulates myocardial injury by secreting paracrine factors, The Journal of Clinical Investigation, 121, 1894, 10.1172/JCI45529 Zhou, 2012, Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes, Journal of Molecular and Cellular Cardiology, 52, 43, 10.1016/j.yjmcc.2011.08.020 Zhou, 2015, Long non coding RNA MALAT1 promotes tumor growth and metastasis by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma, Scientific Reports, 5