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; ≈44×106 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%–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+ 223±49–4415±866/106 cardiomyocytes, P<0.05). In hibernating hearts, icMSCs increased Ki67+ cardiomyocytes (410±83–2460±610/106 nuclei, P<0.05) and phospho-histone H3–positive cardiomyocytes (9±5–116±12/106 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.
- Received April 14, 2010.
- Revision received August 19, 2011.
- Accepted August 22, 2011.
- © 2011 American Heart Association, Inc.