title: Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure.
abstract: In this study, we tested whether the human heart possesses a cardiac stem cell (CSC) pool that promotes regeneration after infarction. For this purpose, CSC growth and senescence were measured in 20 hearts with acute infarcts, 20 hearts with end-stage postinfarction cardiomyopathy, and 12 control hearts. CSC number increased markedly in acute and, to a lesser extent, in chronic infarcts. CSC growth correlated with the increase in telomerase-competent dividing CSCs from 1.5% in controls to 28% in acute infarcts and 14% in chronic infarcts. The CSC mitotic index increased 29-fold in acute and 14-fold in chronic infarcts. CSCs committed to the myocyte, smooth muscle, and endothelial cell lineages increased approximately 85-fold in acute infarcts and approximately 25-fold in chronic infarcts. However, p16(INK4a)-p53-positive senescent CSCs also increased and were 10%, 18%, and 40% in controls, acute infarcts, and chronic infarcts, respectively. Old CSCs had short telomeres and apoptosis involved 0.3%, 3.8%, and 9.6% of CSCs in controls, acute infarcts, and chronic infarcts, respectively. These variables reduced the number of functionally competent CSCs from approximately 26,000/cm3 of viable myocardium in acute to approximately 7,000/cm3 in chronic infarcts, respectively. In seven acute infarcts, foci of spontaneous myocardial regeneration that did not involve cell fusion were identified. In conclusion, the human heart possesses a CSC compartment, and CSC activation occurs in response to ischemic injury. The loss of functionally competent CSCs in chronic ischemic cardiomyopathy may underlie the progressive functional deterioration and the onset of terminal failure.
authors.affiliation: Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.forename: Daniele
authors.initials: D
authors.lastname: Torella
authors.forename: Farooq
authors.initials: F
authors.lastname: Sheikh
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.forename: Daria
authors.initials: D
authors.lastname: Nurzynska
authors.forename: Furio
authors.initials: F
authors.lastname: Silvestri
authors.forename: C Alberto
authors.initials: CA
authors.lastname: Beltrami
authors.forename: Rossana
authors.initials: R
authors.lastname: Bussani
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins; D006321:Heart / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008938:Mitosis / Q000502:physiology; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000166:cytology*; D012038:Regeneration / Q000502:physiology*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000502:physiology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D019098:Telomerase