Interacting Resident Epicardium-Derived Fibroblasts and Recruited Bone Marrow Cells Form Myocardial Infarction Scar

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:65

Article

Ruiz-Villalba, Adrian^1,2  Simon, Ana M.³  Pogontke, Cristina^1,4  Castillo, Maria I.^1,4  Abizanda, Gloria³  Pelacho, Beatriz⁵  Sanchez-Dominguez, Rebeca^6,7  Segovia, Jose C.^6,7  Prosper, Felipe³  Perez-Pomares, Jose M.^1,4 

[1] Univ Malaga, Dept Anim Biol, Fac Sci, E-29071 Malaga, Spain

[2] Univ Amsterdam, AMC, Dept Anat Embryol & Physiol, Amsterdam, Netherlands

[3] Univ Navarra, Dept Hematol, Univ Navarra Clin, CIMA, E-31080 Pamplona, Spain

[4] Andalusian Ctr Nanomed & Biotechnol, Campanillas, Malaga, Spain

[5] Univ Navarra, Stem Cell Therapy Area, Fdn Appl Med Res, E-31080 Pamplona, Spain

[6] Ctr Invest Energet Medioambientales & Tecnol, Ctr Invest Biomed Red Enfermedades Raras, Differentiat & Cytometry Unit, Hematopoiet Innovat Therapies Div, Madrid, Spain

[7] Inst Invest Sanitaria Fdn Jimenez Diaz, Adv Therapies Mixed Unit, Madrid, Spain

关键词: cardiomyocyte;    cell therapy;    fibrosis;    hematopoietic progenitor;    ischemia;   

DOI  :  10.1016/j.jacc.2015.03.520

来源: Elsevier

【 摘 要 】

BACKGROUND Although efforts continue to find new therapies to regenerate infarcted heart tissue, knowledge of 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 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 MI. This response is disease-specific, because angiotensin II-induced pressure overload does not trigger significant 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, 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 postventricular remodeling and may contribute to the development of new therapies to treat this disease. (C) 2015 by the American College of Cardiology Foundation.

【 授权许可】

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