title: Differential expression of embryonic epicardial progenitor markers and localization of cardiac fibrosis in adult ischemic injury and hypertensive heart disease.
abstract: During embryonic heart development, the transcription factors Tcf21, Wt1, and Tbx18 regulate activation and differentiation of epicardium-derived cells, including fibroblast lineages. Expression of these epicardial progenitor factors and localization of cardiac fibrosis were examined in mouse models of cardiovascular disease and in human diseased hearts. Following ischemic injury in mice, epicardial fibrosis is apparent in the thickened layer of subepicardial cells that express Wt1, Tbx18, and Tcf21. Perivascular fibrosis with predominant expression of Tcf21, but not Wt1 or Tbx18, occurs in mouse models of pressure overload or hypertensive heart disease, but not following ischemic injury. Areas of interstitial fibrosis in ischemic and hypertensive hearts actively express Tcf21, Wt1, and Tbx18. In all areas of fibrosis, cells that express epicardial progenitor factors are distinct from CD45-positive immune cells. In human diseased hearts, differential expression of Tcf21, Wt1, and Tbx18 also is detected with epicardial, perivascular, and interstitial fibrosis, indicating conservation of reactivated developmental mechanisms in cardiac fibrosis in mice and humans. Together, these data provide evidence for distinct fibrogenic mechanisms that include Tcf21, separate from Wt1 and Tbx18, in different fibroblast populations in response to specific types of cardiac injury.
authors.affiliation: The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, ML 7020, Cincinnati, OH 45229, USA.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Braitsch
authors.forename: Onur
authors.initials: O
authors.lastname: Kanisicak
authors.forename: Jop H
authors.initials: JH
authors.lastname: van Berlo
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000196:embryology / Q000378:metabolism* / Q000473:pathology*; D006333:Heart Failure / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D010496:Pericardium / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D017493:Leukocyte Common Antigens; D020825:T-Box Domain Proteins; D025721:WT1 Proteins; C420983:Tbx18 protein, mouse; C112923:Tcf21 protein, mouse
keywords: AngII; BMI; Beta-Galactosidase; CHF; COD; CVD; ECM; EMT; EPDC; EndMT; Epicardium-derived cells; Fibrosis; HHD; Heart disease; I/R; IF; LV; MI; MSC; PFA; RV; SM; TAC; Tbx18; Tcf21; Wilms' tumor 1; Wt1; alpha Smooth Muscle Actin; angiotensin II; body mass index; cardiovascular disease; cause of death; congestive heart failure; endothelial–mesenchymal transition; epicardium-derived cell; epithelial–mesenchymal transition; extracellular matrix; hypertensive heart disease; immunofluorescence; ischemia/reperfusion; left ventricle; mesenchymal stem cell; myocardial infarction; paraformaldehyde; right ventricle; smooth muscle; transverse aortic constriction; αSMA; βGal