医学
生物标志物
间充质干细胞
冲程(发动机)
磁共振成像
神经学
临床试验
随机对照试验
代理终结点
磁共振弥散成像
内科学
中风恢复
临床终点
细胞外小泡
神经可塑性
肿瘤科
胃肠病学
作者
Oh Young Bang,Eun Hee Kim,Yeon Hee Cho,Mi Jeong Oh,Jong-Won Chung,Won Hyuk Chang,Yun Hee Kim,Seong Wook Yang,Michael Chopp
出处
期刊:Stroke
[Ovid Technologies (Wolters Kluwer)]
日期:2022-03-28
标识
DOI:10.1161/strokeaha.121.036545
摘要
Background: Mesenchymal stem cells (MSCs) secrete trophic factors and extracellular vesicles (EVs). However, the level and role of EVs after MSC therapy in patients with stroke are unknown. We investigated whether circulating EVs and trophic factors are increased after MSCs and are related to the therapeutic benefits in the STARTING-2 trial (Stem Cell Application Researches and Trials in Neurology-2) participants. Methods: In this prospective randomized controlled trial, patients with chronic major stroke were assigned, in a 2:1 ratio, to receive autologous MSC intravenous injection (MSC group, n=39) or standard treatment (control group, n=15) and followed for 3 months. Detailed clinical assessment and neuroplasticity on diffusion tensor image and resting-state functional magnetic resonance imaging were evaluated. Serial samples were collected, before/after MSCs therapy. The primary outcome measure was circulating factors that are associated with the clinical improvement in the Fugl-Meyer Assessment (secondary end point of the trial) and neuroplasticity on diffusion tensor image and resting-state functional magnetic resonance imaging. Additional outcome measures were microRNAs and trophic factors enriched in the plasma EVs, obtained using quantitative polymerase chain reaction and ELISA, respectively. Results: Circulating EV levels were increased ≈5-fold (mean±SD, from 2.7×10 9 ±2.2×10 9 to 1.3×10 10 ±1.7×10 10 EVs/mL) within 24 hours after injection of MSCs ( P =0.001). After adjustment of age, sex, baseline stroke severity, and the time interval from stroke onset to treatment, only the EV number was independently associated with improvement in motor function (odds ratio, 5.718 for EV number Log [95% CI, 1.144–28.589]; P =0.034). Diffusion tensor image and resting-state functional magnetic resonance imaging showed that integrity of the ipsilesional corticospinal tract and intrahemispheric motor network were significantly correlated with circulating EV levels, respectively ( P <0.05). MicroRNAs related to neurogenesis/neuroplasticity (eg, microRNA-18a-5p) were significantly increased in circulating EVs after MSC therapy ( P =0.0479). In contrast, trophic factor levels were not changed after MSC therapy. Conclusions: This trial is the first to show that treatment of ischemic stroke patients with MSCs significantly increases circulating EVs, which were significantly correlated with improvement in motor function and magnetic resonance imaging indices of plasticity. Registration: URL: https://wwww.clinicaltrials.gov ; Unique identifier: NCT01716481.
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