title: Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar.
abstract: BACKGROUND
  Although efforts continue to find new therapies to regenerate infarcted heart tissue, knowledge of the cellular and molecular mechanisms involved remains poor.
  
  
  OBJECTIVE
  This study sought to identify the origin of cardiac fibroblasts (CFs) in the infarcted heart to better understand the pathophysiology of ventricular remodeling following myocardial infarction (MI).
  
  
  METHODS
  Permanent genetic tracing of epicardium-derived cell (EPDC) and bone marrow-derived blood cell (BMC) lineages was established using Cre/LoxP technology. In vivo gene and protein expression studies, as well as in vitro cell culture assays, were developed to characterize EPDC and BMC interaction and properties.
  
  
  RESULTS
  EPDCs, which colonize the cardiac interstitium during embryogenesis, massively differentiate into CFs after MI. This response is disease-specific, because angiotensin II-induced pressure overload does not trigger significant EPDC fibroblastic differentiation. The expansion of epicardial-derived CFs follows BMC infiltration into the infarct site; the number of EPDCs equals that of BMCs 1 week post-infarction. BMC-EPDC interaction leads to cell polarization, packing, massive collagen deposition, and scar formation. Moreover, epicardium-derived CFs display stromal properties with respect to BMCs, contributing to the sustained recruitment of circulating cells to the damaged zone and the cardiac persistence of hematopoietic progenitors/stem cells after MI.
  
  
  CONCLUSIONS
  EPDCs, but not BMCs, are the main origin of CFs in the ischemic heart. Adult resident EPDC contribution to the CF compartment is time- and disease-dependent. Our findings are relevant to the understanding of post-MI ventricular remodeling and may contribute to the development of new therapies to treat this disease.
authors.affiliation: Department of Animal Biology, Faculty of Sciences, University of Málaga, Málaga, Spain; Department of Anatomy, Embryology and Physiology, AMC-University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Adrián
authors.initials: A
authors.lastname: Ruiz-Villalba
authors.affiliation: Department of Hematology, Clínica Universitaria de Navarra-CIMA, Universidad de Navarra, Pamplona, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Simón
authors.affiliation: Department of Animal Biology, Faculty of Sciences, University of Málaga, Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology, Campanillas (Málaga), Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pogontke
authors.affiliation: Department of Animal Biology, Faculty of Sciences, University of Málaga, Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology, Campanillas (Málaga), Spain.
authors.forename: María I
authors.initials: MI
authors.lastname: Castillo
authors.affiliation: Department of Hematology, Clínica Universitaria de Navarra-CIMA, Universidad de Navarra, Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Abizanda
authors.affiliation: Stem Cell Therapy Area, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pelacho
authors.affiliation: Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas-Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain; Advanced Therapies Mixed Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sánchez-Domínguez
authors.affiliation: Differentiation and Cytometry Unit, Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas-Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain; Advanced Therapies Mixed Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: José C
authors.initials: JC
authors.lastname: Segovia
authors.affiliation: Department of Hematology, Clínica Universitaria de Navarra-CIMA, Universidad de Navarra, Pamplona, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.affiliation: Department of Animal Biology, Faculty of Sciences, University of Málaga, Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology, Campanillas (Málaga), Spain. Electronic address: jmperezp@uma.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Pomares
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002921:Cicatrix / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology*; D010496:Pericardium / Q000473:pathology; D020257:Ventricular Remodeling
keywords: cardiomyocyte; cell therapy; fibrosis; hematopoietic progenitor; ischemia