Safety and Feasibility for Pediatric Cardiac Regeneration Using Epicardial Delivery of Autologous Umbilical Cord Blood-Derived Mononuclear Cells Established in a Porcine Model System
Safety and Feasibility for Pediatric Cardiac Regeneration Using Epicardial Delivery of Autologous Umbilical Cord Blood-Derived Mononuclear Cells Established in a Porcine Model System
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DOI：
10.5966/sctm.2014-0195
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发表时间：
2015-02-01
影响因子：
6
通讯作者：
Nelson, Timothy J.
中科院分区：
文献类型：
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作者：
Peral, Susana Cantero;Burkhart, Harold M.;Nelson, Timothy J.
需要手术姑息的先天性心脏病(CHDS)需要新的治疗策略来优化长期结果。尽管有越来越多的证据表明心脏再生，但在儿科环境中，没有关于自体细胞移植的长期安全性研究。本研究旨在建立猪自体脐带血单个核细胞(UCB-MNCs)移植到幼猪右室(RV)的管道，以评价UCB-MNCs移植的可行性和长期安全性。仔猪是通过剖腹产出生的，以便收集脐带血。在达到释放标准后，12只动物在手术前以双盲方式随机分配试验品(n=6)或安慰剂(n=6)。将UCB-MNC(3×10(6)个/kg)或对照(二甲基亚砜，10%)产物直接注入右室心肌内。这些队列在产品交付后进行了3个月的监测，评估了心脏性能、节律和一系列心脏生化标记物，随后进行了末期尸检。没有死亡率与心肌内注射脐带血单个核细胞或安慰剂有关。来自安慰剂组的两只动物在手术后出现局部皮肤感染，对抗生素治疗有反应。电生理评估显示，在为期3个月的研究中，两组患者均未出现心律失常。细胞治疗组中的两只动物在围手术期出现了一过性亚临床心律失常，可能是因为对麻醉的夸大反应。总体而言，这项研究表明，在儿科环境下，自体脐血单核细胞可以安全地收集和手术输送。安全性简介为针对青少年心脏RV的基于细胞的治疗奠定了基础，并旨在加速基于细胞的治疗进入冠心病的临床试验。
Congenital heart diseases (CHDs) requiring surgical palliation mandate new treatment strategies to optimize long-term outcomes. Despite the mounting evidence of cardiac regeneration, there are no long-term safety studies of autologous cell-based transplantation in the pediatric setting. We aimed to establish a porcine pipeline to evaluate the feasibility and long-term safety of autologous umbilical cord blood mononuclear cells (UCB-MNCs) transplanted into the right ventricle (RV) of juvenile porcine hearts. Piglets were born by caesarean section to enable UCB collection. Upon meeting release criteria, 12 animals were randomized in a double-blinded fashion prior to surgical delivery of test article (n = 6) or placebo (n = 6). The UCB-MNC (3 X 10(6) cells per kilogram) or control (dimethyl sulfoxide, 10%) products were injected intramyocardially into the RV under direct visualization. The cohorts were monitored for 3 months after product delivery with assessments of cardiac performance, rhythm, and serial cardiac biochemical markers, followed by terminal necropsy. No mortalities were associated with intramyocardial delivery of UCB-MNCs or placebo. Two animals from the placebo group developed local skin infection after surgery that responded to antibiotic treatment. Electrophysiological assessments revealed no arrhythmias in either group throughout the 3-month study. Two animals in the cell-therapy group had transient, subclinical dysrhythmia in the perioperative period, likely because of an exaggerated response to anesthesia. Overall, this study demonstrated that autologous UCB-MNCs can be safely collected and surgically delivered in a pediatric setting. The safety profile establishes the foundation for cell-based therapy directed at the RV of juvenile hearts and aims to accelerate cell-based therapies toward clinical trials for CHD.