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J Am Coll Cardiol. 2015 May 19;65(19):2057-66. doi: 10.1016/j.jacc.2015.03.520.

Interacting resident epicardium-derived fibroblasts and recruited bone marrow cells form myocardial infarction scar.

Author information

1
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.
2
Department of Hematology, Clínica Universitaria de Navarra-CIMA, Universidad de Navarra, Pamplona, Spain.
3
Department of Animal Biology, Faculty of Sciences, University of Málaga, Málaga, Spain; Andalusian Center for Nanomedicine and Biotechnology, Campanillas (Málaga), Spain.
4
Stem Cell Therapy Area, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
5
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.
6
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.

Abstract

BACKGROUND:

Although efforts continue to find new therapies to regenerate infarcted heart tissue, knowledge of the cellular and molecular mechanisms involved remains poor.

OBJECTIVES:

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.

KEYWORDS:

cardiomyocyte; cell therapy; fibrosis; hematopoietic progenitor; ischemia

PMID:
25975467
DOI:
10.1016/j.jacc.2015.03.520
[Indexed for MEDLINE]
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