VA WNY Health Care System, Buffalo, NY, USA.
Circ Res. 2011 Oct 14;109(9):1044-54. doi: 10.1161/CIRCRESAHA.111.245969. Epub 2011 Sep 1.
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.
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.
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.
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.
间充质干细胞（MSCs）可改善梗死后的功能，但其作用机制尚不清楚，且减少疤痕体积、心肌细胞增殖和灌注的重要性尚不确定。
本研究旨在验证以下假设，即 MSCs 通过刺激旁分泌依赖性冬眠心肌中的心肌细胞增殖来动员骨髓祖细胞，从而改善功能。
在仪器植入 4 个月后，患有慢性冬眠心肌的猪接受了自体冠状动脉内 MSCs（icMSCs；≈44×10^6 个细胞，n=10）治疗，并在之后的 6 周内进行了研究。将生理和免疫组织化学发现与未治疗的冬眠动物（n=7）、假正常动物（n=5）和 icMSC 治疗的假正常动物（n=6）进行了比较。在冬眠心肌中，icMSCs 增加了功能（左前降支冠状动脉的壁增厚百分比从 24±4%增加到 43±5%，P<0.05），尽管左前降支冠状动脉血流储备（腺苷/休息）仍然严重受损（1.2±0.1 与 1.2±0.1）。icMSC 给药后，循环 cKit+和 CD133+骨髓祖细胞短暂增加，相应增加了心肌 cKit+/CD133+和 cKit+/CD133-骨髓祖细胞（总 cKit+从 223±49 增加到 4415±866/10^6 心肌细胞，P<0.05）。在冬眠心脏中，icMSCs 增加了 Ki67+心肌细胞（从 410±83 增加到 2460±610/10^6 核，P<0.05）和磷酸化组蛋白 H3 阳性心肌细胞（从 9±5 增加到 116±12/10^6 核，P<0.05）。心肌细胞核数（从 75336±5037 增加到 114424±9564 个/ mm^3，P<0.01）和左心室质量（从 2.5±0.1 增加到 2.8±0.1 g/kg，P<0.05）增加，但心肌细胞变小（14.5±0.4 与 16.5±0.4 μm，P<0.05），这支持内源性心肌细胞增殖。在假正常动物中，icMSCs 增加了心肌中的骨髓祖细胞，但对心肌细胞增殖或局部功能没有影响。
我们的结果表明，icMSCs 可改善冬眠心肌的功能，而不依赖于冠状动脉血流或减少疤痕体积。这是通过刺激心肌细胞增殖来实现的，这导致了 cKit+/CD133+骨髓祖细胞和 cKit+/CD133-固有干细胞的增加，从而增加了心肌细胞数量并减少了细胞肥大。
