Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury
Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury
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DOI：
10.1016/j.expneurol.2014.06.009
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发表时间：
2014-11-01
影响因子：
5.3
通讯作者：
Heijnen, Cobi J.
中科院分区：
文献类型：
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作者：
Donega, Vanessa;Nijboer, Cora H.;Heijnen, Cobi J.
我们小组之前的工作表明，鼻内 MSC 治疗可减少新生小鼠缺氧缺血 (HI) 脑损伤后的病变体积并改善运动和认知行为。我们的目的是确定鼻内给药后 MSC 迁移的动力学，以及 MSC 对病变部位神经发生过程和神经胶质增生的早期影响。 在 9 日龄小鼠中诱导 HI 脑损伤，并在 HI 后 10 天鼻内给药 MSC。通过免疫荧光和 MRI 分析研究 MSC 迁移动力学。 MSC 与 HI 脑提取物共培养后，通过 qPCR 分析测定 BDNF 和 NGF 基因表达。巢蛋白。双皮质素。随着时间的推移，评估了 NeuN、GFAP、Iba-1 和 M1/M2 表型表达。MRI 和免疫组织化学分析显示，MSC 在鼻内给药后 2 小时内就已经到达病变部位。给药后 12 小时，病变部位的 MSC 数量达到峰值，并在 72 小时显着下降。在 SVZ 中施用 MSC 后 1 至 3 天，DCX+ 细胞的数量增加。在MSC治疗后3至5天，病变处的GFAP(+)/nestin(+)和DCX+表达增加。 NeuN(+) 细胞的数量在 5 天内增加，导致鼻内 MSC 给药后 18 天体感皮层和海马体急剧再生。有趣的是，当体外暴露于 HI 脑提取物时，MSC 表达显着更多的 BDNF 基因。此外。 MSC 治疗导致病变周围的神经胶质疤痕消失，表现为反应性星形胶质细胞和小胶质细胞的减少以及小胶质细胞向 M2 表型的极化。鉴于目前缺乏治疗策略，我们认为鼻内 MSC 给药是一种强大的治疗选择，通过其对病变的功能性修复（以皮质和海马结构的再生和神经胶质增生的减少为代表）。 (C) 2014 年作者。由爱思唯尔公司出版
Previous work from our group has shown that intranasal MSC-treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Our aim was to determine the kinetics of MSC migration after intranasal administration, and the early effects of MSCs on neurogenic processes and gliosis at the lesion site.HI brain injury was induced in 9-day-old mice and MSCs were administered intranasally at 10 days post-HI. The kinetics of MSC migration were investigated by immunofluorescence and MRI analysis. BDNF and NGF gene expression was determined by qPCR analysis following MSC co-culture with HI brain extract. Nestin. Doublecortin. NeuN, GFAP, Iba-1 and M1/M2 phenotypic expression was assessed over time.MRI and immunohistochemistry analyses showed that MSCs reach the lesion site already within 2 h after intranasal administration. At 12 h after administration the number of MSCs at the lesion site peaks and decreases significantly at 72 h. The number of DCX+ cells increased 1 to 3 days after MSC administration in the SVZ. At the lesion, GFAP(+)/nestin(+) and DCX+ expression increased 3 to 5 days after MSC-treatment. The number of NeuN(+) cells increased within 5 days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18 days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore. MSC-treatment resulted in the resolution of the glial scar surrounding the lesion, represented by a decrease in reactive astrocytes and microglia and polarization of microglia towards the M2 phenotype.In view of the current lack of therapeutic strategies, we propose that intranasal MSC administration is a powerful therapeutic option through its functional repair of the lesion represented by regeneration of the cortical and hippocampal structure and decrease of gliosis. (C) 2014 The Authors. Published by Elsevier Inc.