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

摘要

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; approximately 44 x10(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 mum, 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.