Department of Rehabilitation Medicine, CHA Gumi Medical Center, CHA University College of Medicine, Gumi, Gyeongsangbukdo, Republic of Korea.
Rehabilitation and Regeneration Research Center, CHA University, Seongnam, Republic of Korea.
Sci Rep. 2020 Mar 10;10(1):4446. doi: 10.1038/s41598-020-61441-0.
In a clinical trial of cerebral palsy, the level of plasma interleukin-8 (IL-8) was increased, correlated with motor improvement, after human umbilical cord blood mononuclear cell (hUCBC) infusion. This study aimed to elucidate the role of IL-8 in the therapeutic effects of hUCBCs in a mouse model of hypoxic-ischaemic brain injury (HI). In P7 HI mouse brains, hUCBC administration at day 7 after HI upregulated the gene expression of Cxcl2, the mouse IL-8 homologue and increased the expression of its receptor, CXCR2. hUCBC administration restored the sequential downstream signalling axis of p-p38/p-MAPKAPK2, NFκB, and angiogenic factors, which were downregulated by HI. An in vitro assay revealed the downregulation of the angiogenic pathway by CXCR2 knockdown and p38 inhibition. In vivo p38 inhibition prior to hUCBC administration in HI mouse brains produced identical results. Behavioural outcomes revealed a therapeutic effect (ps < 0.01) of hUCBC or IL-8 administration, which was correlated with decreases in infarct size and angiogenic findings in the striatum. In conclusion, the response of the host to hUCBC administration in mice upregulated Cxcl2, which led to the activation of the IL-8-mediated p-p38 signalling pathway. The upregulation of the downstream pathway and angiogenic growth factors via NFκB can be inferred to be the potential therapeutic mechanism of hUCBCs.
在一项脑瘫的临床试验中，人脐血单个核细胞（hUCBC）输注后，血浆白细胞介素-8（IL-8）水平升高，与运动改善相关。本研究旨在阐明 IL-8 在 hUCBC 治疗缺氧缺血性脑损伤（HI）小鼠模型中的作用。在 P7 HI 小鼠脑内，HI 后第 7 天给予 hUCBC 治疗可上调 Cxcl2 的基因表达，即小鼠 IL-8 同源物，并增加其受体 CXCR2 的表达。hUCBC 治疗可恢复 HI 下调的 p-p38/p-MAPKAPK2、NFκB 和血管生成因子的序贯下游信号通路。体外试验显示 CXCR2 敲低和 p38 抑制可下调血管生成通路。在 HI 小鼠脑内 hUCBC 治疗前进行体内 p38 抑制可产生相同的结果。行为学结果显示 hUCBC 或 IL-8 治疗具有治疗作用（ps < 0.01），这与纹状体梗死面积减少和血管生成发现相关。总之，宿主对小鼠 hUCBC 治疗的反应上调了 Cxcl2，从而导致 IL-8 介导的 p-p38 信号通路的激活。通过 NFκB 上调下游通路和血管生成生长因子可推断为 hUCBC 的潜在治疗机制。
