Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) promote neurological recovery after middle cerebral artery occlusion (MCAO) in young rodents. Ischemic stroke mainly affects aged humans. MSC-sEV effects on stroke recovery in aged rodents had not been assessed. In a head-to-head comparison, we exposed young (4–5 months) and aged (19–20 months) male Sprague–Dawley rats to permanent distal MCAO. At 24 h, 3 and 7 days post-stroke, vehicle or MSC-sEVs (2 × 10⁶ or 2 × 10⁷ MSC equivalents/kg) were intravenously administered. Neurological deficits, ischemic injury, brain inflammatory responses, post-ischemic angiogenesis, and endogenous neurogenesis were evaluated over 28 days. Post-MCAO, aged vehicle-treated rats exhibited more severe motor-coordination deficits evaluated by rotating pole and cylinder tests and larger brain infarcts than young vehicle-treated rats. Although infarct volume was not influenced by MSC-sEVs, sEVs at both doses effectively reduced motor-coordination deficits in young and aged rats. Brain macrophage infiltrates in periinfarct tissue, which were evaluated as marker of a recovery-aversive inflammatory environment, were significantly stronger in aged than young vehicle-treated rats. sEVs reduced brain macrophage infiltrates in aged, but not young rats. The tolerogenic shift in immune balance paved the way for structural brain tissue remodeling. Hence, sEVs at both doses increased periinfarct angiogenesis evaluated by CD31/BrdU immunohistochemistry in young and aged rats, and low-dose sEVs increased neurogenesis in the subventricular zone examined by DCX/BrdU immunohistochemistry. Our study provides robust evidence that MSC-sEVs promote functional neurological recovery and brain tissue remodeling in aged rats post-stroke. This study encourages further proof-of-concept studies in clinic-relevant stroke settings.

从间充质基质细胞 (MSCs) 获得的小细胞外囊泡 (sEVs) 可促进年轻啮齿动物大脑中动脉闭塞 (MCAO) 后的神经功能恢复。缺血性中风主要影响老年人。尚未评估 MSC-sEV 对老年啮齿动物中风恢复的影响。在头对头比较中，我们将年轻（4-5 个月）和老年（19-20 个月）雄性 Sprague-Dawley 大鼠暴露于永久性远端 MCAO。在中风后 24 小时、3 天和 7 天，车辆或 MSC-sEV（2 × 10 ⁶或 2 × 10 ⁷MSC当量/kg)被静脉内施用。在 28 天内评估了神经功能缺损、缺血性损伤、脑炎症反应、缺血后血管生成和内源性神经发生。MCAO 后，与年轻的载体处理的大鼠相比，通过旋转杆和圆柱体测试评估的老年载体治疗大鼠表现出更严重的运动协调缺陷和更大的脑梗塞。虽然梗死体积不受 MSC-sEVs 的影响，但两种剂量的 sEVs 都有效地减少了年轻和老年大鼠的运动协调缺陷。脑巨噬细胞浸润在梗死周围组织中，被评估为厌恶恢复的炎症环境的标志物，在老年大鼠中明显强于接受载体治疗的年轻大鼠。sEVs 减少了老年大鼠的脑巨噬细胞浸润，而不是年轻大鼠。免疫平衡的耐受性转变为结构性脑组织重塑铺平了道路。因此，两种剂量的 sEV 均增加了年轻和老年大鼠 CD31/BrdU 免疫组织化学评估的梗塞周围血管生成，而低剂量 sEV 增加了 DCX/BrdU 免疫组织化学检查的脑室下区的神经发生。我们的研究提供了强有力的证据，表明 MSC-sEV 可促进中风后老年大鼠的功能性神经恢复和脑组织重塑。这项研究鼓励在临床相关的中风环境中进行进一步的概念验证研究。通过 DCX/BrdU 免疫组织化学检查，低剂量 sEV 增加了脑室下区的神经发生。我们的研究提供了强有力的证据，表明 MSC-sEV 可促进中风后老年大鼠的功能性神经恢复和脑组织重塑。这项研究鼓励在临床相关的中风环境中进行进一步的概念验证研究。通过 DCX/BrdU 免疫组织化学检查，低剂量 sEV 增加了脑室下区的神经发生。我们的研究提供了强有力的证据，表明 MSC-sEV 可促进中风后老年大鼠的功能性神经恢复和脑组织重塑。这项研究鼓励在临床相关的中风环境中进行进一步的概念验证研究。