title: Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice.
abstract: The mammalian heart has long been considered a postmitotic organ, implying that the total number of cardiomyocytes is set at birth. Analysis of cell division in the mammalian heart is complicated by cardiomyocyte binucleation shortly after birth, which makes it challenging to interpret traditional assays of cell turnover [Laflamme MA, Murray CE (2011) Nature 473(7347):326-335; Bergmann O, et al. (2009) Science 324(5923):98-102]. An elegant multi-isotope imaging-mass spectrometry technique recently calculated the low, discrete rate of cardiomyocyte generation in mice [Senyo SE, et al. (2013) Nature 493(7432):433-436], yet our cellular-level understanding of postnatal cardiomyogenesis remains limited. Herein, we provide a new line of evidence for the differentiated α-myosin heavy chain-expressing cardiomyocyte as the cell of origin of postnatal cardiomyogenesis using the "mosaic analysis with double markers" mouse model. We show limited, life-long, symmetric division of cardiomyocytes as a rare event that is evident in utero but significantly diminishes after the first month of life in mice; daughter cardiomyocytes divide very seldom, which this study is the first to demonstrate, to our knowledge. Furthermore, ligation of the left anterior descending coronary artery, which causes a myocardial infarction in the mosaic analysis with double-marker mice, did not increase the rate of cardiomyocyte division above the basal level for up to 4 wk after the injury. The clonal analysis described here provides direct evidence of postnatal mammalian cardiomyogenesis.
authors.affiliation: Departments of Pathology and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; shah.ali@gmail.com irv@stanford.edu rardehali@mednet.ucla.edu.
authors.forename: Shah R
authors.initials: SR
authors.lastname: Ali
authors.affiliation: Department of Biology andHoward Hughes Medical Institute, Stanford University, Stanford, CA 94305; and.
authors.forename: Simon
authors.initials: S
authors.lastname: Hippenmeyer
authors.affiliation: Departments of Pathology and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Lily V
authors.initials: LV
authors.lastname: Saadat
authors.affiliation: Department of Biology andHoward Hughes Medical Institute, Stanford University, Stanford, CA 94305; and.
authors.forename: Liqun
authors.initials: L
authors.lastname: Luo
authors.affiliation: Departments of Pathology and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; shah.ali@gmail.com irv@stanford.edu rardehali@mednet.ucla.edu.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Department of Internal Medicine, Division of Cardiology, andBroad Stem Cell Research Center, University of California at Los Angeles School of Medicine, Los Angeles, CA, 90095 shah.ali@gmail.com irv@stanford.edu rardehali@mednet.ucla.edu.
authors.forename: Reza
authors.initials: R
authors.lastname: Ardehali
mesh_terms: D000375:Aging; D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002455:Cell Division; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006321:Heart / Q000254:growth & development; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009030:Mosaicism; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D011995:Recombination, Genetic; D012038:Regeneration; D019076:Transgenes
chemical_list: D049452:Green Fluorescent Proteins
keywords: aging; cardiovascular progenitors; heart development; regeneration