title: Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1.
abstract: Stem cell antigen-1 (Sca-1) has been used to identify cardiac stem cells in the mouse heart. To investigate the function of Sca-1 in aging and during the cardiac adaptation to stress, we used Sca-1-deficient mice. These mice developed dilated cardiomyopathy [end-diastolic left ventricular diameter at 18 wk of age: wild-type (WT) mice, 4.2 mm ± 0.3; Sca-1-knockout (Sca-1-KO) mice, 4.6 mm ± 0.1; ejection fraction: WT mice, 51.1 ± 2.7%; Sca-1-KO mice, 42.9 ± 2.7%]. Furthermore, the hearts of mice lacking Sca-1 demonstrated exacerbated susceptibility to pressure overload [ejection fraction after transaortic constriction (TAC): WT mice, 43.5 ± 3.2%; Sca-1-KO mice, 30.8% ± 4.0] and increased apoptosis, as shown by the 2.5-fold increase in TUNEL(+) cells in Sca-1-deficient hearts under stress. Sca-1 deficiency affected primarily the nonmyocyte cell fraction. Indeed, the number of Nkx2.5(+) nonmyocyte cells, which represent a population of cardiac precursor cells (CPCs), was 2-fold smaller in Sca-1 deficient neonatal hearts. In vitro, the ability of CPCs to differentiate into cardiomyocytes was not affected by Sca-1 deletion. In contrast, these cells demonstrated unrestricted differentiation into cardiomyocytes. Interestingly, proliferation of cardiac nonmyocyte cells in response to stress, as judged by BrdU incorporation, was higher in mice lacking Sca-1 (percentages of BrdU(+) cells in the heart after TAC: WT mice, 4.4 ± 2.1%; Sca-1-KO mice, 19.3 ± 4.2%). These data demonstrate the crucial role of Sca-1 in the maintenance of cardiac integrity and suggest that Sca-1 restrains spontaneous differentiation in the precursor population. The absence of Sca-1 results in uncontrolled precursor recruitment, exhaustion of the precursor pool, and cardiac dysfunction.
authors.affiliation: Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rosenblatt-Velin
authors.forename: Sandy
authors.initials: S
authors.lastname: Ogay
authors.forename: Allison
authors.initials: A
authors.lastname: Felley
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000950:Antigens, Ly / Q000235:genetics* / Q000502:physiology*; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004452:Echocardiography; D006706:Homeostasis / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins