Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Seoul 135-710, Korea.
Stroke. 2013 Feb;44(2):497-504. doi: 10.1161/STROKEAHA.112.679092. Epub 2013 Jan 3.
Severe intraventricular hemorrhage (IVH) in premature infants and the ensuing posthemorrhagic hydrocephalus cause significant mortality and neurological disabilities, and there are currently no effective therapies. This study determined whether intraventricular transplantation of human umbilical cord blood-derived mesenchymal stem cells prevents posthemorrhagic hydrocephalus development and attenuates brain damage after severe IVH in newborn rats.
To induce severe IVH, 100 μL of blood was injected into each lateral ventricle of postnatal day 4 (P4) Sprague-Dawley rats. Human umbilical cord blood-derived mesenchymal stem cells or fibroblasts (1 × 10(5)) were transplanted intraventricularly under stereotaxic guidance at P6. Serial brain MRI and behavioral function tests, such as the negative geotaxis test and rotarod test, were performed. At P32, brain tissue and cerebrospinal fluid were obtained for histological and biochemical analyses.
Intraventricular transplantation of umbilical cord blood-derived mesenchymal stem cells, but not fibroblasts, prevented posthemorrhagic hydrocephalus development and significantly attenuated impairment on behavioral tests; the increased terminal deoxynycleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling-positive cells; increased expression of inflammatory cytokines, such as interleukin-1α, interleukin-1β, interleukin-6, and tumor necrosis factor-α; increased astrogliosis; and reduced corpus callosal thickness and myelin basic protein expression after inducing severe IVH.
Intraventricular transplantation of umbilical cord blood-derived mesenchymal stem cells significantly attenuated the posthemorrhagic hydrocephalus and brain injury after IVH. This neuroprotective mechanism appears to be mediated by the anti-inflammatory effects of these cells.
早产儿严重脑室出血（IVH）和随之发生的出血后脑积水会导致显著的死亡率和神经功能障碍，目前尚无有效的治疗方法。本研究旨在确定是否可以通过向新生大鼠 IVH 后严重 IVH 模型的侧脑室中移植人脐带来源的间充质干细胞（MSCs）来预防出血后脑积水的发生并减轻脑损伤。
在新生后第 4 天（P4）的 Sprague-Dawley 大鼠中，通过立体定向引导将 100μL 的血液注入每侧侧脑室，以诱导严重 IVH。在 P6 时，通过立体定向引导将人脐带来源的 MSCs 或成纤维细胞（1×105）移植到侧脑室中。进行连续的脑 MRI 和行为功能测试，如负趋地性测试和转棒测试。在 P32 时，获取脑组织和脑脊液进行组织学和生化分析。
与成纤维细胞相比，脑室移植人脐带来源的 MSCs 可预防出血后脑积水的发生，并显著减轻行为测试的损伤；增加末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记阳性细胞；增加炎症细胞因子（如白细胞介素-1α、白细胞介素-1β、白细胞介素-6 和肿瘤坏死因子-α）的表达；增加星形胶质细胞增生；并减轻诱导严重 IVH 后胼胝体厚度和髓鞘碱性蛋白表达的减少。
脑室移植人脐带来源的 MSCs 可显著减轻 IVH 后出血性脑积水和脑损伤。这种神经保护机制似乎是由这些细胞的抗炎作用介导的。
