Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
Department of Biomedical Science, CHA University, Seongnam, Republic of Korea.
Exp Mol Med. 2018 Apr 13;50(4):1-12. doi: 10.1038/s12276-018-0041-1.
The human umbilical cord is a promising source of mesenchymal stromal cells (MSCs). Intravenous administration of human umbilical cord-derived MSCs (IV-hUMSCs) showed a favorable effect in a rodent stroke model by a paracrine mechanism. However, its underlying therapeutic mechanisms must be determined for clinical application. We investigated the therapeutic effects and mechanisms of our good manufacturing practice (GMP)-manufactured hUMSCs using various cell doses and delivery time points in a rodent model of stroke. IV-hUMSCs at a dose of 1 × 10 cells at 24 h after stroke improved functional deficits and reduced neuronal damage by attenuation of post-ischemic inflammation. Transcriptome and immunohistochemical analyses showed that interleukin-1 receptor antagonist (IL-1ra) was highly upregulated in ED-1-positive inflammatory cells in rats treated with IV-hUMSCs. Treatment with conditioned medium of hUMSCs increased the expression of IL-1ra in a macrophage cell line via activation of cAMP-response element-binding protein (CREB). These results strongly suggest that the attenuation of neuroinflammation mediated by endogenous IL-1ra is an important therapeutic mechanism of IV-hUMSCs for the treatment of stroke.
人脐带是间充质基质细胞（MSCs）的有前途的来源。静脉内给予人脐带来源的 MSCs（IV-hUMSCs）通过旁分泌机制在啮齿动物中风模型中显示出有利的效果。然而，为了临床应用，必须确定其潜在的治疗机制。我们使用各种细胞剂量和输送时间点在中风啮齿动物模型中研究了我们制造实践良好规范（GMP）制造的 hUMSCs 的治疗效果和机制。中风后 24 小时给予 1×10 个细胞剂量的 IV-hUMSCs 通过减轻缺血后炎症来改善功能缺陷和减少神经元损伤。转录组和免疫组织化学分析表明，在接受 IV-hUMSCs 治疗的大鼠中，ED-1 阳性炎症细胞中白细胞介素 1 受体拮抗剂（IL-1ra）高度上调。hUMSC 条件培养基通过激活 cAMP 反应元件结合蛋白（CREB）增加巨噬细胞系中 IL-1ra 的表达。这些结果强烈表明，内源性 IL-1ra 介导的神经炎症减弱是 IV-hUMSCs 治疗中风的重要治疗机制。
