Autologous Mesenchymal Stem Cells Mobilize cKit+ and CD133+ Bone Marrow Progenitor Cells and Improve Regional Function in Hibernating Myocardium

Rationale: Mesenchymal stem cells (MSCs) improve function after infarction, but their mechanism of action remains unclear, and the importance of reduced scar volume, cardiomyocyte proliferation, and perfusion is uncertain. Objective: The present study was conducted to test the hypothesis that MSCs mobilize bone marrow progenitor cells and improve function by stimulating myocyte proliferation in collateral-dependent hibernating myocardium. Methods and Results: Swine with chronic hibernating myocardium received autologous intracoronary MSCs (icMSCs; approximate to 44x10(6) cells, n=10) 4 months after instrumentation and were studied up to 6 weeks later. Physiological and immunohistochemical findings were compared with untreated hibernating animals (n=7), sham-normal animals (n=5), and icMSC-treated sham-normal animals (n=6). In hibernating myocardium, icMSCs increased function (percent wall thickening of the left anterior descending coronary artery 24 +/- 4% to 43 +/- 5%, P<0.05), although left anterior descending coronary artery flow reserve (adenosine/rest) remained critically impaired (1.2 +/- 0.1 versus 1.2 +/- 0.1). Circulating cKit(+) and CD133(+) bone marrow progenitor cells increased transiently after icMSC administration, with a corresponding increase in myocardial cKit(+)/CD133(+) and cKit(+)/CD133(-) bone marrow progenitor cells (total cKit(+) from 223 +/- 49 to 4415 +/- 866/10(6) cardiomyocytes, P<0.05). In hibernating hearts, icMSCs increased Ki67(+) cardiomyocytes (from 410 +/- 83 to 2460 +/- 610/10(6) nuclei, P<0.05) and phospho-histone H3-positive cardiomyocytes (from 9 +/- 5 to 116 +/- 12/10(6) nuclei, P<0.05). Myocyte nuclear number (from 75 336 +/- 5037 to 114 424 +/- 9564 nuclei/mm(3), P<0.01) and left ventricular mass (from 2.5 +/- 0.1 to 2.8 +/- 0.1 g/kg, P<0.05) increased, yet myocytes were smaller (14.5 +/- 0.4 versus 16.5 +/- 0.4 mu m, P<0.05), which supports endogenous cardiomyocyte proliferation. In sham-normal animals, icMSCs increased myocardial bone marrow progenitor cells with no effect on myocyte proliferation or regional function. Conclusions: Our results indicate that icMSCs improve function in hibernating myocardium independent of coronary flow or reduced scar volume. This arises from stimulation of myocyte proliferation with increases in cKit(+)/CD133(+) bone marrow progenitor cells and cKit(+)/CD133(-) resident stem cells, which increase myocyte number and reduce cellular hypertrophy. (Circ Res. 2011;109:1044-1054.)