Donor Age Negatively Influences Cytoprotective but Not Proangiogenic Paracrine Properties of Human Mesenchymal Stem Cells.

Background: In animal models mesenchymal stem cells (MSC) repair infarcted hearts mainly through cytoprotective paracrine mechanisms. For translational purposes, it is essential to establish if donor age may influence the paracrine properties of MSC. Accordingly, we compared the cardioprotective and proangiogenic effects mediated by MSC from subjects of different age. Methods: fetal MSC (F-MSC) were isolated from human placenta, adult MSC from the bone marrow of young (yBM-MSC; age65) donors. Rat cardiomyocytes (CMC) were exposed to hypoxia (6h)/reoxygenation(18h) (H/R) in the presence of control medium (CTRL-M) or medium conditioned by F-MSC (F-CM), yBM-MSC (y-CM) or oBM-MSC (o-CM). CMC viability was measured by MTS assay, apoptosis by TUNEL staining and Caspase3 activation. EPC migration and tube formation were determined. Myocardial infarction (MI) was induced in rats by temporary ligation of the coronary artery. Saline, F-CM or o-CM was injected at the border zone. Infarct size, apoptotic index and vascular density were determined at 48h. Results: compared with CTRL-M, both F-CM (+45%) and y-CM (+33%) increased CMC viability in vitro (p<0.017), while o-CM had no effect. F-CM reduced the number of TUNEL+ CMC (-91% vs CTRL-M, -89% vs o-CM; p<0.001). The y-CM also reduced CMC apoptosis (-67.5% vs CTRL-M, p<0.01; -64% vs o-CM, p<0.01), while o-CM did not. Caspase-3 activation was prevented by F-CM and y-CM but not by o-CM. At the contrary, EPC migration and tube formation were equally enhanced by F-CM, y-CM and o-CM. In vivo, F-CM significantly reduced the apoptotic index vs both saline (-42%; p<0.001) and o-CM (-23.6%; p<0.01) and prevented Caspase-3 activation. Consistently, infarct size was significantly reduced by F-CM, while o-CM had no effect. F-CM and o-CM equally increased the number of vessels by 18.5% (p<0.05) and 20% (p<0.05) vs saline. Conclusions: cytoprotective but not proangiogenic paracrine properties of human MSC are negatively influenced by donor age. Our data strongly suggest that, in elderly patients, autologous MSC therapy may represent an effective proangiogenic treatment for chronic myocardial ischemia but not a good cardioprotective strategy for ischemia/reperfusion injury.