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 hibernating 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/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 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.