Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury
Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury
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DOI：
10.1371/journal.pone.0090953
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发表时间：
2014-03-12
期刊：
影响因子：
3.7
通讯作者：
Borlongan, Cesar V.
中科院分区：
文献类型：
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作者：
Acosta, Sandra A.;Tajiri, Naoki;Borlongan, Cesar V.
创伤性脑损伤（TBI）与神经炎症、使人衰弱的感觉-运动缺陷以及学习和记忆障碍相关。基于细胞的疗法目前正在研究用于治疗神经创伤，因为它们能够分泌神经营养因子和抗炎细胞因子，可以调节与TBI中发现的慢性神经炎症相关的不利环境。同时，通过粒细胞集落刺激因子（G-CSF）刺激和动员来自骨髓的内源性干/祖细胞成为慢性TBI的有吸引力的治疗干预。在这里，我们测试了在TBI的急性期联合治疗人脐带血细胞（hUCB）和G-CSF的潜力，以抵消慢性TBI的进行性继发性影响使用控制皮质撞击模型。在CCI中度TBI后7天，用单独的盐水、G-CSF+盐水、hUCB+盐水或hUCB+G-CSF处理四个不同组的成年Sprague道利大鼠。TBI后8周，通过免疫组织化学技术收集大脑以分析海马细胞损失、神经炎症反应和神经发生。结果显示，暴露于TBI与盐水治疗的大鼠表现出广泛的神经炎症，受损的内源性神经发生在DG和SVZ，和严重的海马细胞损失。与单独的盐水相比，hUCB单一疗法抑制神经炎症，几乎使神经发生正常化，并减少海马细胞损失。G-CSF单药治疗产生了部分和短暂的获益，其特征在于纹状体、DG、SVZ和胼胝体和穹窿中的神经炎症水平较低，神经发生适度，海马细胞损失中度减少。另一方面，hUCB+G-CSF的联合治疗显示出协同作用，其强烈地抑制神经炎症，同时增强内源性神经发生并减少海马细胞损失。伴随着联合治疗，运动功能的有力和持久的恢复，在单药治疗条件下是中度或短暂的。这些结果表明，联合治疗，而不是单一治疗似乎是最佳的废除慢性TBI的组织病理学和运动障碍。
Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI.