Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement.
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. Support 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 paracrine mechanisms of myocardial protection and functional improvement.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Massimiliano
M
Gnecchi
Huamei
H
He
Nicolas
N
Noiseux
Olin D
OD
Liang
Lunan
L
Zhang
Fulvio
F
Morello
Hui
H
Mu
Luis G
LG
Melo
Richard E
RE
Pratt
Joanne S
JS
Ingwall
Victor J
VJ
Dzau
D000818:Animals; D019610:Cytoprotection / Q000502:physiology*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D019899:Paracrine Communication; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013947:Thymosin / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099201:Thymosin beta(4)
D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D013947:Thymosin; D042461:Vascular Endothelial Growth Factor A; D000099201:Thymosin beta(4)