title: The hypoxic epicardial and subepicardial microenvironment.
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 on [corrected] 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.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Fatih
authors.initials: F
authors.lastname: Kocabas
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Mahmoud
authors.forename: Drazen
authors.initials: D
authors.lastname: Sosic
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015687:Cell Hypoxia; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D010477:Perfusion; D010496:Pericardium / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D014162:Transfection
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen