对心肌活力和干细胞植入的直接评估显示受损心肌得以挽救。
Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium.
作者信息
Kim Paul J, Mahmoudi Morteza, Ge Xiaohu, Matsuura Yuka, Toma Ildiko, Metzler Scott, Kooreman Nigel G, Ramunas John, Holbrook Colin, McConnell Michael V, Blau Helen, Harnish Phillip, Rulifson Eric, Yang Phillip C
机构信息
From the Division of Cardiovascular Medicine, Department of Medicine, Stanford University Medical Center, CA (P.J.K., M.M., X.G., Y.M., I.T., S.M., N.G.K., M.V.M., E.R., P.C.Y.); Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA (J.R., C.H., H.B.); and Eagle Vision Pharmaceutical Corporation, Exton, PA (P.H.).
出版信息
Circ Res. 2015 Mar 27;116(7):e40-50. doi: 10.1161/CIRCRESAHA.116.304668. Epub 2015 Feb 5.
RATIONALE
The mechanism of functional restoration by stem cell therapy remains poorly understood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and precardiac properties. In this study, the restorative effects of 3 AMC-derived subpopulations were examined in a murine myocardial injury model: (1) unselected AMCs, (2) ckit(+)AMCs, and (3) AMC-derived induced pluripotent stem cells (MiPSCs).
OBJECTIVE
To determine the differential restorative effects of the AMC-derived subpopulations in the murine myocardial injury model using multimodality imaging.
METHODS AND RESULTS
SCID (severe combined immunodeficiency) mice underwent left anterior descending artery ligation and were divided into 4 treatment arms: (1) normal saline control (n=14), (2) unselected AMCs (n=10), (3) ckit(+)AMCs (n=13), and (4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular function, whereas bioluminescence imaging assessed stem cell engraftment during a 4-week period. Immunohistological labeling and reverse transcriptase polymerase chain reaction of the explanted myocardium were performed. The unselected AMC and ckit(+)AMC-treated mice demonstrated transient left ventricular functional improvement. However, the MiPSCs exhibited a significantly greater increase in left ventricular function compared with all the other groups during the entire 4-week period. Left ventricular functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSC-treated animals lacked any evidence of de novo cardiac differentiation.
CONCLUSION
The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.
原理
干细胞疗法实现功能恢复的机制仍知之甚少。新型锰增强磁共振成像和生物发光报告基因成像分别用于追踪心肌活力和细胞植入情况。人胎盘来源的羊膜间充质干细胞（AMCs）具有独特的免疫调节和心脏前体细胞特性。在本研究中，在小鼠心肌损伤模型中检测了3种AMC衍生亚群的恢复效果：（1）未分选的AMCs，（2）c-kit(+)AMCs，以及（3）AMC衍生的诱导多能干细胞（MiPSCs）。
目的
使用多模态成像确定AMC衍生亚群在小鼠心肌损伤模型中的不同恢复效果。
方法与结果
严重联合免疫缺陷（SCID）小鼠接受左冠状动脉前降支结扎，并分为4个治疗组：（1）生理盐水对照组（n = 14），（2）未分选的AMCs组（n = 10），（3）c-kit(+)AMCs组（n = 13），以及（4）MiPSCs组（n = 11）。心脏磁共振成像评估心肌活力和左心室功能，而生物发光成像评估4周内的干细胞植入情况。对外植心肌进行免疫组织学标记和逆转录聚合酶链反应。未分选的AMC和c-kit(+)AMC治疗的小鼠左心室功能出现短暂改善。然而，在整个4周期间，MiPSCs组左心室功能的改善明显大于所有其他组。左心室功能改善与心肌活力增加和干细胞持续植入相关。接受MiPSCs治疗的动物没有任何新生心脏分化的证据。
结论
MiPSCs中观察到的功能恢复表现为心肌活力增加和持续植入且无新生心脏分化，表明受损心肌得到挽救。
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