Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury.
Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury.
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DOI：
10.3171/2014.11.jns14770
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发表时间：
2015-04
影响因子：
4.1
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Chopp M;Meng Y;Katakowski M;Xin H;Mahmood A;Xiong Y
移植多能间充质基质细胞（MSCs）促进大鼠创伤性脑损伤（TBI）后的功能恢复。在这里，我们测试了一种新的假设，即全身给予从MSC产生的无细胞外泌体促进TBI后大鼠的功能恢复和神经血管重塑。对Wistar大鼠进行TBI，然后在24小时后尾静脉注射100 μg来源于MSC的外来体蛋白或等体积的载体磷酸盐缓冲盐水（n = 8/组）。采用改良Morris水迷宫、神经功能缺损评分和足错试验评价认知和感觉运动功能的恢复情况。在TBI后35天处死动物。进行组织学和免疫组织化学分析以测量病变体积、神经血管重塑（血管生成和神经发生）和神经炎症。与盐水处理的对照相比，外泌体处理的TBI大鼠在34-35天时通过Morris水迷宫测试测量的空间学习（p < 0.05）和感觉运动功能恢复（即，在损伤后14-35天观察到神经功能缺损和足错频率降低（p < 0.05）。外泌体治疗显著增加了病变边界区和齿状回中新生内皮细胞的数量，显著增加了齿状回中新生未成熟和成熟神经元的数量，并减少了神经炎症。我们首次证明，MSC产生的外泌体至少部分地通过促进内源性血管生成和神经发生以及减少TBI后大鼠的炎症来有效改善功能恢复。因此，MSC产生的外泌体可能为TBI和可能的其他神经系统疾病提供新的无细胞疗法。
Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). Here, we test a novel hypothesis that systemic administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI. Wistar rats were subjected to TBI followed by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle phosphate-buffered saline (n = 8/group) 24 hours later. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, neurological severity score and footfault tests were performed. Animals were sacrificed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation. Compared with saline-treated controls, exosome-treated TBI rats showed significant improvement in spatial learning at 34-35 days measured by the Morris water maze test (p < 0.05), and sensorimotor functional recovery, i.e., reduced neurological deficits and footfault frequency, observed at 14-35 days post injury (p < 0.05). Exosome treatment significantly increased the number of newborn endothelial cells in the lesion boundary zone and dentate gyrus, and significantly increased the number of newborn immature and mature neurons in the dentate gyrus as well as reduced neuroinflammation. We, for the first time, demonstrate that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly other neurological diseases.