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

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


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.

MeSH terms

  • Animals
  • Bone Marrow Cells / pathology*
  • Cell Differentiation
  • Cells, Cultured
  • Cicatrix / etiology
  • Cicatrix / pathology*
  • Cicatrix / physiopathology
  • Disease Models, Animal
  • Fibroblasts / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / complications
  • Myocardial Infarction / pathology*
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / pathology*
  • Pericardium / pathology
  • Ventricular Remodeling*