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Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen‐1
Author(s) -
RosenblattVelin Nathalie,
Ogay Sandy,
Felley Allison,
Stanford William L.,
Pedrazzini Thierry
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-189605
Subject(s) - pressure overload , stem cell , medicine , immunology , cardiology , biology , microbiology and biotechnology , heart failure , cardiac hypertrophy
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.—Rosenblatt‐Velin, N., Ogay, S., Felley, A., Stanford, W. L., Pedrazzini, T. Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen‐1. FASEB J. 26, 229–239 (2012). www.fasebj.org