The Hypoxic Epicardial and Subepicardial Microenvironment

  • Fatih Kocabas
  • Ahmed I. Mahmoud
  • Drazen Sosic
  • Enzo R. Porrello
  • Rui Chen
  • Joseph A. Garcia
  • Ralph J. DeBerardinis
  • Hesham A. Sadek
Article

Abstract

Recent reports indicate that the adult mammalian heart is capable of limited, but measurable, cardiomyocyte turnover. While the lineage origin of the newly formed cardiomyocytes is not entirely understood, mounting evidence suggest that the epicardium and subepicardium may represent an important source of cardiac stem or progenitor cells. Stem cell niches are characterized by low oxygen tension, where stem cells preferentially utilize cytoplasmic glycolysis to meet their energy demands. However, it is unclear if the heart harbors similar hypoxic regions, or whether these regions house metabolically distinct cardiac progenitor populations. Here we identify the epicardium and subepicardium as the cardiac hypoxic niche-based capillary density quantification, and localization of Hif-1α in the uninjured heart. We further demonstrate that this hypoxic microenvironment houses a metabolically distinct population of glycolytic progenitor cells. Finally, we show that Hif-1α regulates the glycolytic phenotype and progenitor properties of these cells. These findings highlight important anatomical and functional properties of the epicardial and subepicardial microenvironment, and the potential role of hypoxia signaling in regulation of cardiac progenitors.

Keywords

Epicardium Subepicardium Cardiac progenitors Hypoxic microenvironment 

Supplementary material

12265_2012_9366_Fig5_ESM.jpg (89 kb)
Figure S1

Endomucin staining. Adult heart sections were stained with the endothelial marker endomucin and detected using DAB chromogen. Images of four-chamber view adult heart sections were quantified for capillaries for cell layers at five different zones in the coronal plane (base to apex) and seven different zones in the horizontal plane (endocardium to epicardium). (JPEG 33 kb)

12265_2012_9366_MOESM1_ESM.tif (5.7 mb)
High resolution image. (TIFF 5824 kb)
12265_2012_9366_Fig6_ESM.jpg (35 kb)
Figure S2

Quantification of Hif-1α expression in ventricular epicardium and subepicardium. The number of Hif-1α-expressing cells in the epicardium and subepicardium was quantified. The majority of ventricular epicardial cells expressed Hif-1α, while only a small percentage of subepicardial and myocardial myocytes and non-myocytes expressed Hif-1α. (JPEG 34 kb)

12265_2012_9366_MOESM2_ESM.tif (21.8 mb)
High resolution image. (TIFF 22344 kb)
12265_2012_9366_Fig7_ESM.jpg (33 kb)
Figure S3

Atrial Hif-1α expression. The majority of atrial cells express Hif-1α. Hif-1α (green), Tnnt2 (red), and DAPI (blue). (JPEG 88 kb)

12265_2012_9366_MOESM3_ESM.tif (7.4 mb)
High resolution image. (TIFF 7613 kb)

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Fatih Kocabas
    • 1
  • Ahmed I. Mahmoud
    • 1
  • Drazen Sosic
    • 2
  • Enzo R. Porrello
    • 2
  • Rui Chen
    • 1
  • Joseph A. Garcia
    • 1
  • Ralph J. DeBerardinis
    • 3
  • Hesham A. Sadek
    • 1
  1. 1.Department of Internal Medicine, Division of CardiologyUT Southwestern Medical CenterDallasUSA
  2. 2.Department of Molecular BiologyUT Southwestern Medical CenterDallasUSA
  3. 3.Departments of Pediatrics and GeneticsUT Southwestern Medical CenterDallasUSA

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