Karantalis Vasileios, Suncion-Loescher Viky Y, Bagno Luiza, Golpanian Samuel, Wolf Ariel, Sanina Cristina, Premer Courtney, Kanelidis Anthony J, McCall Frederic, Wang Bo, Balkan Wayne, Rodriguez Jose, Rosado Marcos, Morales Azorides, Hatzistergos Konstantinos, Natsumeda Makoto, Margitich Irene, Schulman Ivonne Hernandez, Gomes Samirah A, Mushtaq Muzammil, DiFede Darcy L, Fishman Joel E, Pattany Pradip, Zambrano Juan Pablo, Heldman Alan W, Hare Joshua M
The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida.
Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida.
J Am Coll Cardiol. 2015 Nov 3;66(18):1990-1999. doi: 10.1016/j.jacc.2015.08.879.
Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit(+) cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically.
To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy.
Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy.
Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity.
These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.
骨髓间充质干细胞（MSCs）和c-kit(+)心脏干细胞（CSCs）在猪模型和临床试验中均能改善左心室重构。在急性缺血性心脏病的免疫抑制动物中使用异种（人类）细胞，我们先前表明这两种细胞类型具有协同作用。
为了更准确地模拟心力衰竭的临床应用，本研究在慢性缺血性心肌病的非免疫抑制猪模型中测试了自体MSCs和CSCs联合使用是否比单独使用MSCs能更显著地改善心脏功能。
在缺血/再灌注损伤3个月后，哥廷根猪接受经心内膜注射，单独注射MSCs（n = 6）或与心脏来源的CSCs联合注射（n = 8），或注射安慰剂（赋形剂；n = 6）。在基线以及治疗前后使用心脏磁共振评估心脏功能和解剖参数。
与安慰剂相比，两组细胞治疗动物在注射后3个月时瘢痕大小均显著减小（MSCs组 -44.1 ± 6.8%；CSC/MSCs组 -37.2 ± 5.4%；安慰剂组 -12.9 ± 4.2%；p < 0.0001），存活组织增加，壁运动改善。仅在联合治疗的动物中，射血分数（EF）有所改善（MSCs组增加2.9 ± 1.6个EF单位；CSC/MSCs组增加6.9 ± 2.8个EF单位；安慰剂组增加2.5 ± 1.6个EF单位；p = 0.0009），每搏输出量、心输出量和舒张期应变也有所改善，联合治疗组还表现出心肌细胞有丝分裂活性增加。
这些发现表明，MSCs和CSCs之间的相互作用比单独使用MSCs更能增强心脏功能，确立了自体细胞联合策略的安全性，并支持第二代细胞治疗产品的开发。
