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(Circulation Research. 2007;100:536.)
© 2007 American Heart Association, Inc.

Cellular Biology

Adolescent Feline Heart Contains a Population of Small, Proliferative Ventricular Myocytes With Immature Physiological Properties

Xiongwen Chen^*, Rachel M. Wilson^*, Hajime Kubo, Remus M. Berretta, David M. Harris, Xiaoying Zhang, Naser Jaleel, Scott M. MacDonnell, Claudia Bearzi, Jochen Tillmanns, Irina Trofimova, Toru Hosoda, Federico Mosna, Leanne Cribbs, Annarosa Leri, Jan Kajstura, Piero Anversa, Steven R. Houser

From the Cardiovascular Research Center (X.C., R.M.W., H.K., R.M.B., N.J., S.M.M., S.R.H.), Temple University School of Medicine, Philadelphia, Pa; Center for Translational Medicine (D.M.H.), Department of Medicine, Thomas Jefferson University, Philadelphia, Pa; Fox Chase Cancer Center (X.Z.), Philadelphia, Pa; Cardiovascular Research Institute (C.B., J.T., I.T., T.H., F.M., A.L., J.K., P.A.), Department of Medicine, New York Medical College, Valhalla; and Department of Medicine (L.C.), Cardiovascular Institute, Loyola University Medical Center, Maywood, Ill.

Correspondence to Dr Steven R. Houser, Cardiovascular Research Center, Temple University School of Medicine, 3400 North Broad St, Philadelphia, PA 19140. E-mail srhouser{at}temple.edu

Recent studies suggest that rather than being terminally differentiated, the adult heart is a self-renewing organ with the capacity to generate new myocytes from cardiac stem/progenitor cells (CS/PCs). This study examined the hypotheses that new myocytes are generated during adolescent growth, to increase myocyte number, and these newly formed myocytes are initially small, mononucleated, proliferation competent, and have immature properties. Ventricular myocytes (VMs) and cKit⁺ (stem cell receptor) CS/PCs were isolated from 11- and 22-week feline hearts. Bromodeoxyuridine incorporation (in vivo) and p16^INK4a immunostaining were measured to assess myocyte cell cycle activity and senescence, respectively. Telomerase activity, contractions, Ca²⁺ transients, and electrophysiology were compared in small mononucleated (SMMs) and large binucleated (LBMs) myocytes. Heart mass increased by 101% during adolescent growth, but left ventricular myocyte volume only increased by 77%. Most VMs were binucleated (87% versus 12% mononucleated) and larger than mononucleated myocytes. A greater percentage of SMMs was bromodeoxyuridine positive (SMMs versus LBMs: 3.1% versus 0.8%; P<0.05), and p16^INK4a negative and small myocytes had greater telomerase activity than large myocytes. Contractions and Ca²⁺ transients were prolonged in SMMs versus LBMs and Ca²⁺ release was disorganized in SMMs with reduced transient outward current and T-tubule density. The T-type Ca²⁺ current, usually seen in fetal/neonatal VMs, was found exclusively in SMMs and in myocytes derived from CS/PC. Myocyte number increases during adolescent cardiac growth. These new myocytes are initially small and functionally immature, with patterns of ion channel expression normally found in the fetal/neonatal period

Key Words: new ventricular myocytes • T-type calcium current • cardiac stem cells • calcium

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Big Cells, Little Cells, Stem Cells: Agents of Cardiac Plasticity

Eduardo Marbán
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