Abstract
The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Culture Media, Conditioned / pharmacology
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Female
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Follistatin-Related Proteins / genetics
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Follistatin-Related Proteins / metabolism*
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Humans
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Male
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Mice
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Myoblasts, Cardiac / cytology
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Myoblasts, Cardiac / drug effects
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Myocardial Infarction / genetics
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardium / metabolism*
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Pericardium / cytology
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Pericardium / drug effects
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Pericardium / growth & development*
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Pericardium / metabolism*
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Rats
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Regeneration* / drug effects
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Signal Transduction
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Swine
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Transgenes / genetics
Substances
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Culture Media, Conditioned
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Follistatin-Related Proteins
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Fstl1 protein, mouse
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FSTL1 protein, human