title: Effects of age and heart failure on human cardiac stem cell function.
abstract: Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(Cip1) and p16(INK4a) expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy.
authors.affiliation: Center for Regenerative Medicine, Udine Medical School, Udine, Italy. daniela.cesselli@uniud.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Federica
authors.initials: F
authors.lastname: D'Aurizio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marcon
authors.forename: Natascha
authors.initials: N
authors.lastname: Bergamin
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoletto
authors.forename: Maura
authors.initials: M
authors.lastname: Pandolfi
authors.forename: Elisa
authors.initials: E
authors.lastname: Puppato
authors.forename: Laura
authors.initials: L
authors.lastname: Marino
authors.forename: Sergio
authors.initials: S
authors.lastname: Signore
authors.forename: Ugolino
authors.initials: U
authors.lastname: Livi
authors.forename: Roberto
authors.initials: R
authors.lastname: Verardo
authors.forename: Silvano
authors.initials: S
authors.lastname: Piazza
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.forename: Claudio
authors.initials: C
authors.lastname: Schneider
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Beltrami
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D032383:Myocytes, Cardiac / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000209:etiology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D019098:Telomerase; D016615:Telomere / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase