人类诱导多能干细胞治疗的功能后果：梗死后重构的体内猪心脏中的心肌 ATP 周转率。
Functional consequences of human induced pluripotent stem cell therapy: myocardial ATP turnover rate in the in vivo swine heart with postinfarction remodeling.
机构信息
Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
出版信息
Circulation. 2013 Mar 5;127(9):997-1008. doi: 10.1161/CIRCULATIONAHA.112.000641. Epub 2013 Jan 31.
BACKGROUND
The use of cells derived from human induced pluripotent stem cells as cellular therapy for myocardial injury has yet to be examined in a large-animal model.
METHODS AND RESULTS
Immunosuppressed Yorkshire pigs were assigned to 1 of 3 groups: A myocardial infarction group (MI group; distal left anterior descending coronary artery ligation and reperfusion; n=13); a cell-treatment group (MI with 4×10(6) vascular cells derived from human induced pluripotent stem cells administered via a fibrin patch; n=14); and a normal group (n=15). At 4 weeks, left ventricular structural and functional abnormalities were less pronounced in hearts in the cell-treated group than in MI hearts (P<0.05), and these improvements were accompanied by declines in scar size (10.4±1.6% versus 8.3±1.1%, MI versus cell-treatment group, P<0.05). The cell-treated group displayed a significant increase in vascular density and blood flow (0.83±0.11 and 1.05±0.13 mL·min(-1)·g(-1), MI versus cell-treatment group, P<0.05) in the periscar border zone (BZ), which was accompanied by improvements in systolic thickening fractions (infarct zone, -10±7% versus 5±5%; BZ, 7±4% versus 23±6%; P<0.05). Transplantation of vascular cells derived from human induced pluripotent stem cells stimulated c-kit(+) cell recruitment to BZ and the rate of bromodeoxyuridine incorporation in both c-kit(+) cells and cardiomyocytes (P<0.05). Using a magnetic resonance spectroscopic saturation transfer technique, we found that the rate of ATP hydrolysis in BZ of MI hearts was severely reduced, and the severity of this reduction was linearly related to the severity of the elevations of wall stresses (r=0.82, P<0.05). This decline in BZ ATP utilization was markedly attenuated in the cell-treatment group.
CONCLUSIONS
Transplantation of vascular cells derived from human induced pluripotent stem cells mobilized endogenous progenitor cells into the BZ, attenuated regional wall stress, stimulated neovascularization, and improved BZ perfusion, which in turn resulted in marked increases in BZ contractile function and ATP turnover rate.
背景
使用源自人类诱导多能干细胞的细胞作为细胞疗法治疗心肌损伤尚未在大型动物模型中进行检验。
方法和结果
免疫抑制的约克夏猪被分为 3 组中的 1 组：心肌梗死组（MI 组；左前降支远端结扎和再灌注；n=13）；细胞治疗组（MI 后给予 4×10（6）个源自人类诱导多能干细胞的血管细胞，通过纤维蛋白贴剂给药；n=14）；和正常组（n=15）。4 周时，与 MI 心脏相比，细胞治疗组心脏的左心室结构和功能异常程度较轻（P<0.05），这些改善伴随着瘢痕面积的减少（10.4±1.6%与 8.3±1.1%，MI 与细胞治疗组，P<0.05）。细胞治疗组在疤痕边缘区（BZ）的血管密度和血流显著增加（0.83±0.11 和 1.05±0.13 mL·min(-1)·g(-1)，MI 与细胞治疗组，P<0.05），同时伴有收缩增厚分数的改善（梗死区，-10±7%与 5±5%；BZ，7±4%与 23±6%；P<0.05）。源自人类诱导多能干细胞的血管细胞的移植刺激了 c-kit（+）细胞向 BZ 的募集以及 c-kit（+）细胞和心肌细胞中溴脱氧尿苷掺入的速率（P<0.05）。使用磁共振光谱饱和转移技术，我们发现 MI 心脏 BZ 中的 ATP 水解速率严重降低，这种降低的严重程度与壁应力升高的严重程度呈线性相关（r=0.82，P<0.05）。细胞治疗组明显减轻了 BZ 中 ATP 利用的下降。
结论
源自人类诱导多能干细胞的血管细胞的移植将内源性祖细胞动员到 BZ，减轻了区域性壁应力，刺激了新血管生成，并改善了 BZ 灌注，从而导致 BZ 收缩功能和 ATP 周转率的显著增加。
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