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.
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Acknowledgments
The authors would like to acknowledge Drs. Eric Olson and James Richardson for their valuable input and John Shelton for his assistance with histology. Work in Hesham Sadek's laboratory is supported by grants from the American Heart Association (Fellow to Faculty Award) and the Gilead Sciences Research Scholars Program in Cardiovascular Disease.
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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)
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)
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)
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Kocabas, F., Mahmoud, A.I., Sosic, D. et al. The Hypoxic Epicardial and Subepicardial Microenvironment. J. of Cardiovasc. Trans. Res. 5, 654–665 (2012). https://doi.org/10.1007/s12265-012-9366-7
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DOI: https://doi.org/10.1007/s12265-012-9366-7