Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh School of Medicine, PA (W.Z., H.P., X.H., Y.S., R.A.S., Q.Y., J.L., F.Z., J.C.).
Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (W.Z., H.P., X.H., Y.S., R.A.S., Q.Y., F.Z., J.C.).
Stroke. 2023 Apr;54(4):1088-1098. doi: 10.1161/STROKEAHA.122.041507. Epub 2023 Mar 13.
Stroke is the primary cause of chronic disability in the elderly, as there are no neurorestorative treatments for those who do not qualify for recanalization therapy. Experimental evidence in stroke animals suggests that transplantation of bone marrow-derived human mesenchymal stem cells (hMSCs) holds promise, but hMSC transplantation has not been systematically tested in aged animals. We tested the hypothesis that poststroke hMSC transplantation improves stroke recovery in aged mice by promoting brain repair.
Permanent focal cerebral ischemia was induced in 20-month-old C57BL/6 male mice by distal middle cerebral artery occlusion. Bone marrow-derived hMSCs were expanded in vitro and then administrated intravenously into mice (1×10 cells in PBS) 24 hours after distal middle cerebral artery occlusion. Sensorimotor and cognitive functions, brain atrophy, and brain repair processes (neurogenesis, angiogenesis, oligodendrogenesis) were assessed for up to 56 days after stroke.
Poststroke hMSC transplantation did not mitigate brain atrophy or improve neuronal survival at 56 days after distal middle cerebral artery occlusion. However, hMSC-treated mice displayed superior neurobehavioral performances in the open field, rotarod, adhesive removal, novel object, and Morris water maze tests compared with PBS-treated controls. hMSCs promoted white matter integrity and enhanced angiogenesis and oligodendrogenesis-but not neurogenesis-in the stroke brain. Positive correlations between neurobehavioral performance and brain repair profiles or white matter integrity were observed in stroke mice.
Poststroke hMSC transplantation improves long-term stroke recovery in aged mice, likely via mechanisms involving enhanced microvascular regeneration and white matter restoration.
中风是老年人慢性残疾的主要原因，因为对于不符合再通治疗条件的患者，尚无神经修复治疗方法。中风动物的实验证据表明，骨髓源性人间质干细胞（hMSC）的移植具有前景，但 hMSC 移植尚未在老年动物中进行系统测试。我们通过促进大脑修复来检验 hMSC 移植是否能改善老年中风鼠的中风恢复的假设。
通过远端大脑中动脉闭塞，在 20 月龄 C57BL/6 雄性小鼠中诱导永久性局灶性脑缺血。体外扩增骨髓源性 hMSC，然后在远端大脑中动脉闭塞后 24 小时通过静脉内给予小鼠（PBS 中的 1×10 个细胞）。在中风后长达 56 天评估感觉运动和认知功能、脑萎缩和脑修复过程（神经发生、血管生成、少突胶质发生）。
中风后 hMSC 移植不能减轻远端大脑中动脉闭塞 56 天后的脑萎缩或改善神经元存活。然而，与 PBS 处理的对照组相比，hMSC 治疗的小鼠在开阔场、转棒、粘取物去除、新物体和 Morris 水迷宫测试中显示出更好的神经行为表现。hMSCs 促进了中风大脑的白质完整性，并增强了血管生成和少突胶质发生，但没有促进神经发生。中风小鼠的神经行为表现与脑修复特征或白质完整性之间存在正相关。
中风后 hMSC 移植可改善老年中风鼠的长期中风恢复，可能通过增强微血管再生和白质修复的机制。
