Optimal Timing of Mesenchymal Stem Cell Therapy for Neonatal Intraventricular Hemorrhage
Optimal Timing of Mesenchymal Stem Cell Therapy for Neonatal Intraventricular Hemorrhage
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DOI：
10.3727/096368915x689640
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发表时间：
2016-01-01
影响因子：
3.3
通讯作者：
Chang, Yun Sil
中科院分区：
文献类型：
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作者：
Park, Won Soon;Sung, Se In;Chang, Yun Sil
我们最近发现，脑室内移植人脐带血（UCB）来源的间充质干细胞（MSC）显着减轻出血后脑积水（PHH）和脑损伤后，严重的脑室出血（IVH）的新生大鼠幼崽。本研究的目的是优化MSC移植治疗严重IVH的时机。通过在出生后第4天（P4）向Sprague-Dawley大鼠的每个心室注射100 μ l血液来诱导严重IVH。将人脐带血来源的MSC（10 μ l生理盐水中的1 × 10（5）个细胞）脑室内移植。在P6早期或P11晚期进行立体定位引导。进行系列脑MRI和行为功能测试，如阴性趋地性和旋转棒测试。在P32，获得脑组织样品用于组织学和生化分析。诱导重度IVH后，侧脑室内移植MSCs可显著减轻PHH的发展、行为障碍、增加细胞凋亡和星形胶质细胞增生、减少胼胝体厚度和脑髓鞘形成，并在P6时上调炎性细胞因子，包括白细胞介素（IL）-1 α、IL-1 β、IL-6和肿瘤坏死因子-α（TNF-α），但在P11时则无此作用。脑室内移植人脐血间充质干细胞能以时间依赖的方式减轻新生大鼠重度脑室出血后的PHH和脑损伤。只有在诱导后2天早期给药时才显示出显著的神经保护作用，而在诱导严重IVH后7天晚期给药时则没有。
We recently showed that intraventricular transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuated posthemorrhagic hydrocephalus (PHH) and brain injury after severe intraventricular hemorrhage (IVH) in newborn rat pups. The purpose of this study was to optimize the timing of MSC transplantation for severe IVH. Severe IVH was induced by injecting 100 mu l of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). Human UCB-derived MSCs (1 x 10(5) cells in 10 mu l of normal saline) were transplanted intraventricularly under. stereotaxic guidance either early at P6 or late at P11. Serial brain MRIs and behavioral function tests, such as negative geotaxis and rotarod tests, were performed. At P32, brain tissue samples were obtained for histological and biochemical analyses. Intracerebroventricular transplantation of MSCs significantly attenuated the development of PHH, behavioral impairment, increased apoptosis and astrogliosis, reduced corpus callosum thickness and brain myelination, and upregulated inflammatory cytokines including interleukin (IL)-1 alpha, IL-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) at P6 but not at P11 after induction of severe IVH. Intracerebroventricular transplantation of human UCB -derived MSCs attenuated PHH and brain injury after severe IVH in newborn rats in a time-dependent manner. Significant neuroprotection was only demonstrated when administered early at 2 days after induction but not late at 7 days after induction of severe IVH.