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.