Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product.
Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product.
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DOI：
10.1016/j.ymthe.2018.03.017
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发表时间：
2018-07-05
期刊：
影响因子：
--
通讯作者：
Baker AH
中科院分区：
文献类型：
--
作者：
MacAskill MG;Saif J;Condie A;Jansen MA;MacGillivray TJ;Tavares AAS;Fleisinger L;Spencer HL;Besnier M;Martin E;Biglino G;Newby DE;Hadoke PWF;Mountford JC;Emanueli C;Baker AH
多能干细胞衍生的分化内皮细胞在心血管系统的再生医学中具有很高的潜力。为了将人类干细胞衍生的内皮细胞产品（hESC-ECP）用于治疗人类严重肢体缺血（CLI），我们报告了一个良好的生产规范（GMP）兼容的协议和详细的细胞跟踪和疗效数据在多个临床前模型。临床级细胞系RC 11用于产生hESC-ECP，其被鉴定为主要是内皮细胞（60%CD31 +/CD 144+），其余子集表达各种周细胞/间充质干细胞标志物。在肢体缺血的鼠模型中使用MRI、PET和qPCR的细胞追踪证明，在注射后的第7天可检测到hESC-ECP。在几种肢体缺血小鼠模型（免疫功能低下/免疫功能正常小鼠和患有I/II型糖尿病的小鼠）中的有效性证明了血液灌注和毛细血管密度显著增加。总的来说，我们证明了GMP兼容的hESC-ECP，改善了缺血肢体灌注，增加了局部血管生成，而无需植入，为这种疗法的转化铺平了道路。为了将hESC-ECP转化为临床CLI治疗，MacAskill et al.开发了一种用于hESC-ECP生成的稳健的GMP兼容方法。hESC-ECP在缺血肢体内保留了107天，并在有/无完整免疫系统或糖尿病的肢体缺血小鼠模型中显著改善了足部灌注和毛细血管密度。
Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy. To translate hESC-ECP into the clinic for CLI treatment, MacAskill et al. developed a robust, GMP-compatible method for hESC-ECP generation. hESC-ECP remained within ischemic limbs for ∼7 days and significantly improved foot perfusion and capillary density in murine models of limb ischemia with/without an intact immune system or diabetes mellitus.
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