Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Dr, MSC 1363, Bethesda, MD 20892-1363, USA.
Stroke. 2011 Oct;42(10):2932-9. doi: 10.1161/STROKEAHA.110.612788. Epub 2011 Aug 11.
The migratory efficiency of mesenchymal stem cells (MSC) toward cerebral infarct after transplantation is limited. Valproate (VPA) and lithium enhance in vitro migration of MSC by upregulating CXC chemokine receptor 4 and matrix metalloproteinase-9, respectively. Ability of VPA and lithium to promote MSC homing and to improve functional recovery was assessed in a rat model of cerebral ischemia.
MSC primed with VPA (2.5 mmol/L, 3 hours) and/or lithium chloride (2.5 mmol/L, 24 hours) were transplanted into rats 24 hours after transient middle cerebral artery occlusion (MCAO). Neurological function was assessed via rotarod test, Neurological Severity Score, and body asymmetry test for 2 weeks. Infarct volume was analyzed by MRI. The number of homing MSC and microvessel density in the infarcted regions were measured 15 days after MCAO using immunohistochemistry.
Priming with VPA or lithium increased the number of MSC homing to the cerebral infarcted regions, and copriming with VPA and lithium further enhanced this effect. MCAO rats receiving VPA-primed and/or lithium-primed MSC showed improved functional recovery, reduced infarct volume, and enhanced angiogenesis in the infarcted penumbra regions. These beneficial effects of VPA or lithium priming were reversed by AMD3100, a CXC chemokine receptor 4 antagonist, and GM6001, a matrix metalloproteinase inhibitor, respectively.
Priming with VPA and/or lithium promoted the homing and migration ability of MSC, improved functional recovery, reduced brain infarct volume, and enhanced angiogenesis in a rat MCAO model. These effects were likely mediated by VPA-induced CXC chemokine receptor 4 overexpression and lithium-induced matrix metalloproteinase-9 upregulation.
间充质干细胞（MSC）移植后向脑梗死部位迁移的效率有限。丙戊酸（VPA）和锂分别通过上调趋化因子受体 4 和基质金属蛋白酶-9 来增强 MSC 的体外迁移能力。本研究评估了 VPA 和锂促进 MSC 归巢和改善功能恢复的能力，方法是在大鼠脑缺血模型中进行。
将用 VPA（2.5mmol/L，3 小时）和/或氯化锂（2.5mmol/L，24 小时）预处理的 MSC 在短暂性大脑中动脉闭塞（MCAO）后 24 小时移植到大鼠体内。通过转棒试验、神经严重程度评分和身体不对称试验评估神经功能，持续 2 周。用 MRI 分析梗死体积。用免疫组化法测定 MCAO 后 15 天梗死区归巢 MSC 的数量和微血管密度。
VPA 或锂预处理增加了 MSC 向脑梗死区的归巢数量，而 VPA 和锂联合预处理进一步增强了这种效应。接受 VPA 预处理和/或锂预处理 MSC 的 MCAO 大鼠表现出更好的功能恢复，梗死体积减少，梗死半影区血管生成增强。VPA 或锂预处理的这些有益作用分别被 CXCR4 拮抗剂 AMD3100 和基质金属蛋白酶抑制剂 GM6001 逆转。
VPA 和/或锂预处理可促进 MSC 的归巢和迁移能力，改善功能恢复，减少脑梗死体积，并增强大鼠 MCAO 模型中的血管生成。这些作用可能是通过 VPA 诱导的 CXCR4 过表达和锂诱导的基质金属蛋白酶-9 上调介导的。
