Article: article from journal or magazin.
Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Adaptation, Physiological/physiology, Age Factors, Animals, Animals, Newborn, Antigens, Ly/genetics, Antigens, Ly/physiology, Aorta/physiopathology, Apoptosis/physiology, Cardiomyopathy, Dilated/genetics, Cardiomyopathy, Dilated/physiopathology, Cell Differentiation/physiology, Cell Division/physiology, Chronic Disease, Disease Models, Animal, Echocardiography, Homeostasis/physiology, Membrane Proteins/genetics, Membrane Proteins/physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac/cytology, Myocytes, Cardiac/physiology, Regeneration/physiology, Stem Cells/cytology, Stem Cells/physiology, Stress, Physiological/physiology
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