Department of Anesthesiology, 63328Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine.
Department of Nursing, 63267Asia University, Taichung.
Cell Transplant. 2020 Jan-Dec;29:963689720929313. doi: 10.1177/0963689720929313.
Intracranial hemorrhage from stroke and head trauma elicits a cascade of inflammatory and immune reactions detrimental to neurological integrity and function at cellular and molecular levels. This study tested the hypothesis that human umbilical cord-derived mesenchymal stem cell (HUCDMSC) therapy effectively protected the brain integrity and neurological function in rat after acute traumatic brain injury (TBI). Adult male Sprague-Dawley rats ( = 30) were equally divided into group 1 (sham-operated control), group 2 (TBI), and group 3 [TBI + HUCDMSC (1.2 × 10 cells/intravenous injection at 3 h after TBI)] and euthanized by day 28 after TBI procedure. The results of corner test and inclined plane test showed the neurological function was significantly progressively improved from days 3, 7, 14, and 28 in groups 1 and 3 than in group 2, and group 1 than in group 3 (all < 0.001). By day 28, brain magnetic resonance imaging brain ischemic volume was significantly increased in group 2 than in group 3 ( < 0.001). The protein expressions of apoptosis [mitochondrial-bax positive cells (Bax)/cleaved-caspase3/cleaved-poly(adenosine diphosphate (ADP)-ribose) polymerase], fibrosis (Smad3 positive cells (Smad3)/transforming growth factor-β), oxidative stress (NADPH Oxidase 1 (NOX-1)/NADPH Oxidase 2 (NOX-2)/oxidized-protein/cytochrome b-245 alpha chain (p22phox)), and brain-edema/deoxyribonucleic acid (DNA)-damaged biomarkers (Aquaporin-4/gamma H2A histone family member X ( (γ-H2AX)) displayed an identical pattern to neurological function among the three groups (all < 0.0001), whereas the protein expressions of angiogenesis biomarkers (vascular endothelial growth factor/stromal cell-derived factor-1α/C-X-C chemokine receptor type 4 (CXCR4)) significantly increased from groups 1 to 3 (all < 0.0001). The cellular expressions of inflammatory biomarkers (cluster of differentiation 14 (+) cells (CD14+)/glial fibrillary acidic protein positive cells (GFAP+)/ a member of a new family of EGF-TM7 molecules positive cells (F4/80+)) and DNA-damaged parameter (γ-H2AX) exhibited an identical pattern, whereas cellular expressions of neural integrity (hexaribonucleotide Binding Protein-3 positive cells (NeuN+)/nestin+/doublecortin+) exhibited an opposite pattern of neurological function among the three groups (all < 0.0001). Xenogeneic HUCDMSC therapy was safe and it significantly preserved neurological function and brain architecture in rat after TBI.
脑出血脑卒中源于创伤性颅脑损伤，在细胞和分子水平上引发一连串有害的炎症和免疫反应，破坏神经完整性和功能。本研究旨在检验人脐带间充质干细胞（HUCDMSC）治疗是否能有效保护大鼠急性创伤性脑损伤（TBI）后的脑完整性和神经功能。雄性成年 Sprague-Dawley 大鼠（ = 30）等分为三组：1 组（假手术对照）、2 组（TBI）和 3 组（TBI+HUCDMSC[1.2×10 个细胞/静脉注射，TBI 后 3 小时]），并于 TBI 后 28 天处死。转角试验和斜板试验的结果显示，1 组和 3 组的神经功能从第 3、7、14 和 28 天开始，与 2 组相比，以及与 3 组相比，1 组的神经功能均显著逐渐改善（均<0.001）。28 天时，与 3 组相比，2 组的脑磁共振成像脑缺血体积明显增加（<0.001）。凋亡标志物[线粒体 Bax 阳性细胞（Bax）/cleaved-caspase3/cleaved-poly（adenosine diphosphate（ADP）-ribose）polymerase]、纤维化标志物[Smad3 阳性细胞（Smad3）/转化生长因子-β]、氧化应激标志物[NADPH Oxidase 1（NOX-1）/NADPH Oxidase 2（NOX-2）/氧化蛋白/cytochrome b-245 alpha chain（p22phox）]、脑水肿/脱氧核糖核酸（DNA）损伤生物标志物（水通道蛋白-4/γH2A 组蛋白家族成员 X（（γ-H2AX））在三组中的表达模式与神经功能完全一致（均<0.0001），而血管生成生物标志物[血管内皮生长因子/基质细胞衍生因子-1α/C-X-C 趋化因子受体 4（CXCR4）]的蛋白表达从 1 组到 3 组明显增加（均<0.0001）。炎症标志物[CD14+细胞（CD14+）/胶质纤维酸性蛋白阳性细胞（GFAP+）/EGF-TM7 家族新成员 A 阳性细胞（F4/80+）]和 DNA 损伤参数（γ-H2AX）的细胞表达模式完全一致，而神经完整性标志物[六核苷酸结合蛋白-3 阳性细胞（NeuN+）/巢蛋白+/双皮质素+]的细胞表达模式与三组的神经功能呈相反模式（均<0.0001）。异种间充质干细胞治疗是安全的，它能显著改善 TBI 后大鼠的神经功能和脑结构。
