Abuzan Mihaela, Surugiu Roxana, Wang Chen, Mohamud-Yusuf Ayan, Tertel Tobias, Catalin Bogdan, Doeppner Thorsten R, Giebel Bernd, Hermann Dirk M, Popa-Wagner Aurel
Experimental Research Center in Normal and Pathological Aging (ARES), University of Medicine and Pharmacy, Craiova, Romania.
Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Transl Stroke Res. 2025 Jun;16(3):817-830. doi: 10.1007/s12975-024-01266-5. Epub 2024 Sep 7.
Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) have shown considerable promise as restorative stroke treatment. In a head-to-head comparison in mice exposed to transient proximal middle cerebral artery occlusion (MCAO), sEVs obtained from MSCs cultured under hypoxic conditions particularly potently enhanced long-term brain tissue survival, microvascular integrity, and angiogenesis. These observations suggest that hypoxic preconditioning might represent the strategy of choice for harvesting MSC-sEVs for clinical stroke trials. To test the efficacy of hypoxic MSCs in a second stroke model in an additional species, we now exposed 6-8-month-old Sprague-Dawley rats to permanent distal MCAO and intravenously administered vehicle, platelet sEVs, or sEVs obtained from hypoxic MSCs (1% O; 2 × 10 or 2 × 10 cell equivalents/kg) at 24 h, 3, 7, and 14 days post-MCAO. Over 28 days, motor-coordination recovery was evaluated by rotating pole and cylinder tests. Ischemic injury, brain inflammatory responses, and peri-infarct angiogenesis were assessed by infarct volumetry and immunohistochemistry. sEVs obtained from hypoxic MSCs did not influence infarct volume in this permanent MCAO model, but promoted motor-coordination recovery over 28 days at both sEV doses. Ischemic injury was associated with brain ED1 macrophage infiltrates and Iba1 microglia accumulation in the peri-infarct cortex of vehicle-treated rats. Hypoxic MSC-sEVs reduced brain macrophage infiltrates and microglia accumulation in the peri-infarct cortex. In vehicle-treated rats, CD31/BrdU proliferating endothelial cells were found in the peri-infarct cortex. Hypoxic MSC-sEVs increased the number of CD31/BrdU proliferating endothelial cells. Our results provide evidence that hypoxic MSC-derived sEVs potently enhance neurological recovery, reduce neuroinflammation. and increase angiogenesis in rat permanent distal MCAO.
从间充质基质细胞（MSCs）获得的小细胞外囊泡（sEVs）作为中风修复治疗已显示出巨大潜力。在对短暂性大脑中动脉近端闭塞（MCAO）小鼠进行的直接比较中，从在缺氧条件下培养的MSCs获得的sEVs特别有效地增强了长期脑组织存活、微血管完整性和血管生成。这些观察结果表明，缺氧预处理可能是收获用于临床中风试验的MSC-sEVs的首选策略。为了在另一个物种的第二个中风模型中测试缺氧MSCs的疗效，我们现在将6-8个月大的Sprague-Dawley大鼠暴露于永久性大脑中动脉远端闭塞（MCAO），并在MCAO后24小时、3天、7天和14天静脉注射载体、血小板sEVs或从缺氧MSCs获得的sEVs（1%氧气；2×10或2×10细胞当量/千克）。在28天内，通过转棒试验和圆筒试验评估运动协调恢复情况。通过梗死体积测量和免疫组织化学评估缺血性损伤、脑部炎症反应和梗死周围血管生成。在这个永久性MCAO模型中，从缺氧MSCs获得的sEVs不影响梗死体积，但在两种sEV剂量下均促进了28天内的运动协调恢复。缺血性损伤与载体处理大鼠梗死周围皮质中的脑ED1巨噬细胞浸润和Iba1小胶质细胞积累有关。缺氧MSC-sEVs减少了梗死周围皮质中的脑巨噬细胞浸润和小胶质细胞积累。在载体处理的大鼠中，在梗死周围皮质中发现了CD31/BrdU增殖内皮细胞。缺氧MSC-sEVs增加了CD31/BrdU增殖内皮细胞的数量。我们的结果提供了证据，表明缺氧MSC衍生的sEVs能有效增强神经恢复、减少神经炎症并增加大鼠永久性大脑中动脉远端闭塞模型中的血管生成。
