脑内移植人源修饰骨髓基质细胞（SB623）联合跑轮式自主运动对缺血性脑卒中大鼠的协同治疗作用。

Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke.

机构信息

Department of Neurological Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan.

Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan.

出版信息

Stem Cell Res Ther. 2023 Jan 24;14(1):10. doi: 10.1186/s13287-023-03236-4.

DOI:10.1186/s13287-023-03236-4

PMID:36691091

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9872315/

Abstract

BACKGROUND

Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke.

METHODS

Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 10 cells/5 μl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups.

RESULTS

SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05).

CONCLUSIONS

This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

摘要

背景

间充质基质细胞（MSC）移植疗法是一种有前途的中风患者治疗方法。与此同时，物理运动康复可以改善中风引起的神经功能缺损。在这项研究中，我们旨在阐明是否脑内移植人改良骨髓源性 MSC、SB623 细胞，以及结合跑轮（RW）的自愿运动的联合治疗对缺血性中风大鼠模型具有协同治疗作用。

方法

Wistar 大鼠接受右侧短暂性大脑中动脉闭塞（MCAO）。在 MCAO 前 7 天，自愿运动（Ex）组在带有 RW 的笼子中接受训练。在 MCAO 后第 1 天，将 SB623 细胞（4.0×10 个细胞/5μl）立体定向注射到右侧纹状体。在 MCAO 后第 1、7 和 14 天，使用改良神经严重程度评分（mNSS）和圆筒试验进行行为测试。在 MCAO 后第 15 天，对缺血性梗死面积、内源性神经发生、血管生成以及脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）的表达进行 mRNA 水平评估，然后处死大鼠。大鼠被随机分配到以下四组之一：载体、Ex、SB623 和 SB623+Ex 组。

结果

与载体组相比，SB623+Ex 组在 mNSS 中实现了显著的神经恢复（p<0.05）。与其他所有组相比，SB623+Ex 组的脑梗死面积明显减小（p<0.05）。在侧脑室下区（SVZ）和齿状回（DG）中的 BrdU/双皮质素（Dcx）双阳性细胞数量、缺血边界区（IBZ）中的层粘连蛋白阳性区以及 SB623+Ex 组的 BDNF 和 VEGF 的 mRNA 水平均显著高于其他所有组（p<0.05）。