Takemura Mitsuhiro, Sasaki Masanori, Kataoka-Sasaki Yuko, Kiyose Ryo, Nagahama Hiroshi, Oka Shinichi, Ukai Ryo, Yokoyama Takahiro, Kocsis Jeffery D, Ueba Tetsuya, Honmou Osamu
1Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine.
3Department of Neurosurgery, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
J Neurosurg. 2021 Dec 3;137(2):402-411. doi: 10.3171/2021.8.JNS21687. Print 2022 Aug 1.
Stroke is a major cause of long-term disability, and there are few effective treatments that improve function in patients during the chronic phase of stroke. Previous research has shown that single systemic infusion of mesenchymal stem cells (MSCs) improves motor function in acute and chronic cerebral ischemia models in rats. A possible mechanism that could explain such an event includes the enhanced neural connections between cerebral hemispheres that contribute to therapeutic effects. In the present study, repeated infusions (3 times at weekly intervals) of MSCs were administered in a rat model of chronic stroke to determine if multiple dosing facilitated plasticity in neural connections.
The authors induced middle cerebral artery occlusion (MCAO) in rats and, 8 weeks thereafter, used them as a chronic stroke model. The rats with MCAO were randomized and intravenously infused with vehicle only (vehicle group); with MSCs at week 8 (single administration: MSC-1 group); or with MSCs at weeks 8, 9, and 10 (3 times, repeated administration: MSC-3 group) via femoral veins. Ischemic lesion volume and behavioral performance were examined. Fifteen weeks after induction of MCAO, the thickness of the corpus callosum (CC) was determined using Nissl staining. Immunohistochemical analysis of the CC was performed using anti-neurofilament antibody. Interhemispheric connections through the CC were assessed ex vivo by diffusion tensor imaging.
Motor recovery was better in the MSC-3 group than in the MSC-1 group. In each group, there was no change in the ischemic volume before and after infusion. However, both thickness and optical density of neurofilament staining in the CC were greater in the MSC-3 group, followed by the MSC-1 group, and then the vehicle group. The increased thickness and optical density of neurofilament in the CC correlated with motor function at 15 weeks following induction of MCAO. Preserved neural tracts that ran through interhemispheric connections via the CC were also more extensive in the MSC-3 group, followed by the MSC-1 group and then the vehicle group, as observed ex vivo using diffusion tensor imaging.
These results indicate that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. In addition, administration of MSCs is associated with promotion of interhemispheric connectivity through the CC in the chronic phase of cerebral infarction.
中风是导致长期残疾的主要原因，在中风慢性期，几乎没有能改善患者功能的有效治疗方法。先前的研究表明，单次全身输注间充质干细胞（MSC）可改善大鼠急性和慢性脑缺血模型中的运动功能。一种可能解释这一现象的机制包括大脑半球之间增强的神经连接，这有助于产生治疗效果。在本研究中，在慢性中风大鼠模型中进行多次（每周1次，共3次）MSC输注，以确定多次给药是否促进神经连接的可塑性。
作者诱导大鼠大脑中动脉闭塞（MCAO），8周后将其作为慢性中风模型。将MCAO大鼠随机分组，分别经股静脉仅输注溶剂（溶剂组）；在第8周输注MSC（单次给药：MSC-1组）；或在第8、9和10周输注MSC（3次，重复给药：MSC-3组）。检查缺血性病变体积和行为表现。MCAO诱导15周后，采用尼氏染色法测定胼胝体（CC）厚度。使用抗神经丝抗体对CC进行免疫组织化学分析。通过扩散张量成像在体外评估通过CC的半球间连接。
MSC-3组的运动恢复情况优于MSC-1组。每组输注前后缺血体积均无变化。然而，CC中神经丝染色的厚度和光密度在MSC-3组中最大，其次是MSC-1组，然后是溶剂组。CC中神经丝厚度和光密度的增加与MCAO诱导后15周时的运动功能相关。如通过扩散张量成像在体外观察到的，经CC穿过半球间连接的保留神经束在MSC-3组中也更广泛，其次是MSC-1组，然后是溶剂组。
这些结果表明，与单次给药和/或溶剂输注相比，3周内多次全身给予MSC可带来更大的功能改善。此外，在脑梗死慢性期给予MSC与通过CC促进半球间连接有关。
