A Proliferative Burst during Preadolescence Establishes the Final Cardiomyocyte Number

• Type of Material: Article
• Authors: Nawazish Naqvi, Emory University; Ming Li, Victor Chang Cardiac Research Institute; John Calvert, Emory University; Thor Tejada, Emory University; Jonathan P. Lambert, Emory University; Jianxin Wu, Victor Chang Cardiac Research Institute; Scott H. Kesteven, Victor Chang Cardiac Research Institute; Sara R. Holman, Victor Chang Cardiac Research Institute; Torahiro Matsuda, Emory University; Joshua D. Lovelock, Emory University; Wesley W. Howard, Emory University; Siiri E. Iismaa, Victor Chang Cardiac Research Institute; Andrea Y. Chan, Victor Chang Cardiac Research Institute; Brian H. Crawford, Children's Healthcare Atlanta; Mary Wagner, Emory University; David I.K. Martin, Children's Hospital Oakland Research Institute; David J. Lefer, Emory University; Robert M. Graham, Victor Chang Cardiac Research Institute; Ahsan Husain, Emory University
• Language: English
• Date: 2014-05-08
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cell.2014.03.035
• Title of Journal or Parent Work: Cell
• ISSN: 0092-8674
• Volume: 157
• Issue: 4
• Start Page: 795
• End Page: 807
• Grant/Funding Information: This work was supported by: the Department of Medicine, Division of Cardiology, Emory University; the Carlyle Fraser Heart Center, Emory University Hospital Midtown;NIH grants to A.H. (HL079040), J.W.C. (HL098481), M.B.W. (HL088488), and T.T. (T32HL007745); John and Mary Brock Translational Research Fund grant (to A.H.); Regenerative Engineering and Medicine (REM) center at Emory and Georgia Tech grant (to A.H. and N.N.); Emory and Children's Center for Cardiovascular Biology pilot grant (to A.H., N.N., and M.B.W.); American Heart Association Scientist Development Grant (to N.N.); National Health and Medical Research Council of Australia grants (to R.M.G, S.E.I and M.L.); Heart Foundation of Australia grant (to R.M.G., M.L. and S.E.I.); R. T. Hall Estate grant (to R.M.G., M.L., and S.E.I.); and an Australian Research Council Stem Cells Australia, Special Initiative in Stem Cell Science grant (to R.M.G).
• Keywords: CARDIAC-FUNCTION; TRANSGENIC MICE; CONTRACTILITY; Cell Biology; MYOCYTE PROLIFERATION; DNA-SYNTHESIS; Biochemistry & Molecular Biology; OVEREXPRESSION; HYPERTROPHY; Life Sciences & Biomedicine; HEART REGENERATION; Science & Technology; GROWTH-FACTOR-I; THYROID-HORMONE
• Research Categories: Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, we show that a thyroid hormone surge activates the IGF-1/IGF-1-R/Akt pathway on postnatal day 15 and initiates a brief but intense proliferative burst of predominantly binuclear cardiomyocytes. This proliferation increases cardiomyocyte numbers by ∼40%, causing a major disparity between heart and cardiomyocyte growth. Also, the response to cardiac injury at postnatal day 15 is intermediate between that observed at postnatal days 2 and 21, further suggesting persistence of cardiomyocyte proliferative capacity beyond the perinatal period. If replicated in humans, this may allow novel regenerative therapies for heart diseases.