title: Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart.
abstract: Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific α myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.
authors.affiliation: 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kimura
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiao
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Canseco
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Muralidhar
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: SuWannee
authors.initials: S
authors.lastname: Thet
authors.affiliation: Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Yezan
authors.initials: Y
authors.lastname: Abderrahman
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Medicine, VA North Texas Health Care System, 4600 South Lancaster Road, Dallas, Texas 75216, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.affiliation: 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.affiliation: Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Abdelrahman M
authors.initials: AM
authors.lastname: Ashour
authors.affiliation: Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
authors.affiliation: McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Hanquan
authors.initials: H
authors.lastname: Liang
authors.affiliation: McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
authors.affiliation: 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D045522:Recombinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins; D045522:Recombinases