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Evidence supporting paracrine hypothesis for Akt‐modified mesenchymal stem cell‐mediated cardiac protection and functional improvement
Author(s) -
Gnecchi Massimiliano,
He Huamei,
Noiseux Nicolas,
Liang Olin D.,
Zhang Lunan,
Morello Fulvio,
Mu Hui,
Melo Luis G.,
Pratt Richard E.,
Ingwall Joanne S.,
Dzau Victor J.
Publication year - 2006
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.05-5211com
Subject(s) - protein kinase b , paracrine signalling , mesenchymal stem cell , stem cell , pi3k/akt/mtor pathway , microbiology and biotechnology , medicine , endocrinology , biology , signal transduction , receptor
ABSTRACT We previously reported that intramyocardial injection of bone marrow‐derived mesenchymal stem cells overexpressing Akt (Akt‐MSCs) inhibits ventricular remodeling and restores cardiac function measured 2 wk after myocardial infarction. Here, we report that the functional improvement occurs in < 72 h. This early remarkable effect cannot be readily attributed to myocardial regeneration from the donor cells. Thus, we hypothesized that paracrine actions exerted by the cells through the release of soluble factors might be important mechanisms of tissue repair and functional improvement after injection of the Akt‐MSCs. Indeed, in the current study we demonstrate that conditioned medium from hypoxic Akt‐MSCs markedly inhibits hypoxia‐induced apoptosis and triggers vigorous spontaneous contraction of adult rat cardiomyocytes in vitro . When injected into infarcted hearts, the Akt‐MSC conditioned medium significantly limits infarct size and improves ventricular function relative to controls. Sup‐port to the paracrine hypothesis is provided by data showing that several genes, coding for factors (VEGF, FGF‐2, HGF, IGF‐I, and TB4) that are potential mediators of the effects exerted by the Akt‐MSC conditioned medium, are significantly up‐regulated in the Akt‐MSCs, particularly in response to hypoxia. Taken together, our data support Akt‐MSC‐mediated para‐crine mechanisms of myocardial protection and functional improvement.‐Gnecchi, M., He, H., Noiseux, N., Liang, O. D., Zhang, L., Morello, F., Mu, H., Melo, L. G., Pratt, R. E., Ingwall, J. S., Dzau, V. J. Evidence supporting paracrine hypothesis for Akt‐modified mes‐enchymal stem cell‐mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006)