Autologous mesenchymal stem cells mobilize cKit+ and CD133+ bone marrow progenitor cells and improve regional function in hibernating myocardium.

ABSTRACT

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 hibe rnating myocardium. METHODS AND RESULTS: Swine with chronic hibernating myocardium received autologous intracoronary MSCs (icMSCs; ≈44 ×10(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/mm3, 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 µm, 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.