过表达细胞外调节激酶 1/2 的间充质干细胞对大鼠卒中的保护作用。
Protective effects of mesenchymal stem cells overexpressing extracellular regulating kinase 1/2 against stroke in rats.
机构信息
Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China; Department of Anatomy and Neurobiology, Southwest Medical University, Luzhou, 646000, China.
Department of Neurology, Shanghai Tongji hospital, Tongji University School of Medicine, Shanghai, 200065, China.
出版信息
Brain Res Bull. 2019 Jul;149:42-52. doi: 10.1016/j.brainresbull.2019.04.006. Epub 2019 Apr 16.
OBJECTIVE
Although transplantation of bone marrow-derived mesenchymal stem cells (MSCs) has shown beneficial effects on stroke, lower survival of MSCs limits effects. Extracellular regulating kinase 1/2 signaling (ERK1/2) is crucial for cell survival, differentiation, and proliferation. This study was designed to explore whether MSCs modified by over-expressing ERK1/2 may reinforce beneficial effects on stroke in rats.
METHODS
rat MSCs transfected with ERK1/2 and empty lentivirus to generate MSCs overexpressing ERK1/2 (ERK/MSCs) and MSCs (as a control), respectively. In vitro, ERK/MSCs were plated and exposed to glutamate-induced condition, and viability of ERK/MSCs was measured. Furthermore, neural induction of ERK/MSCs was investigated in vitro. Cerebral ischemic rats were induced by occluding middle cerebral artery, and then were stereotaxically injected into ipsilateral right lateral ventricle with ERK/MSCs or MSCs 3 days after stroke and survived for 7 or 14 days after injection.
RESULTS
ERK/MSCs showed better viability in physiological and glutamate-induced neurotoxic conditions compared to MSCs. After neural induction, more neurons were be differentiated from ERK/MSCs than from MSCs. After transplantation, more numbers of grafted cells and improved functional recovery were observed in ERK/MSCs-treated rats compared with MSCs-treated rats. Compared with MSCs treatment, ERK/MSCs treatment significantly increased proliferation of neural stem cells in the subventricle zone (SVZ) and the MAP2/nestin double-labeled cells adjacent to the SVZ, enhanced the numbers of reactive astrocytes while suppressed microglial activation. Besides, TNF-α level was elevated in ERK/MSCs-treated rats.
CONCLUSION
ERK/MSCs transplantation showed better functional recovery after stroke in rats, likely in part through enhancing survival of MSCs and possibly by modulating the proliferation, neuronal de-differentiation and neuroinflammation.
目的
尽管骨髓间充质干细胞（MSCs）移植已显示出对中风的有益影响，但 MSCs 的存活率较低限制了其效果。细胞外调节激酶 1/2 信号（ERK1/2）对细胞存活、分化和增殖至关重要。本研究旨在探讨过表达 ERK1/2 的 MSCs 是否可增强对大鼠中风的有益影响。
方法
用 ERK1/2 和空载慢病毒转染大鼠 MSCs，分别生成过表达 ERK1/2 的 MSCs（ERK/MSCs）和 MSCs（作为对照）。体外，将 ERK/MSCs 铺板并暴露于谷氨酸诱导的条件下，测量 ERK/MSCs 的活力。此外，还研究了 ERK/MSCs 的体外神经诱导。通过阻断大脑中动脉诱导脑缺血大鼠，在中风后 3 天，通过立体定向将 ERK/MSCs 或 MSCs 注射到对侧右侧侧脑室，然后在注射后 7 或 14 天存活。
结果
与 MSCs 相比，ERK/MSCs 在生理和谷氨酸诱导的神经毒性条件下具有更好的活力。神经诱导后，ERK/MSCs 分化出的神经元多于 MSCs。移植后，ERK/MSCs 治疗组大鼠的移植物细胞数量增加，功能恢复改善，优于 MSCs 治疗组。与 MSCs 治疗相比，ERK/MSCs 治疗可显著增加侧脑室下区（SVZ）中神经干细胞的增殖和 SVZ 附近 MAP2/nestin 双标记细胞的数量，增加反应性星形胶质细胞的数量，同时抑制小胶质细胞的激活。此外，ERK/MSCs 治疗组大鼠的 TNF-α水平升高。
结论
ERK/MSCs 移植可改善大鼠中风后的功能恢复，这可能部分是通过增强 MSCs 的存活，可能通过调节增殖、神经元去分化和神经炎症来实现。
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