Arien-Zakay Hadar, Gincberg Galit, Nagler Arnon, Cohen Gadi, Liraz-Zaltsman Sigal, Trembovler Victoria, Alexandrovich Alexander G, Matok Ilan, Galski Hanan, Elchalal Uriel, Lelkes Peter I, Lazarovici Philip, Shohami Esther
1 School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem , Jerusalem, Israel .
J Neurotrauma. 2014 Aug 15;31(16):1405-16. doi: 10.1089/neu.2013.3270. Epub 2014 Jul 14.
Treatment of traumatic brain injury (TBI) is still an unmet need. Cell therapy by human umbilical cord blood (HUCB) has shown promising results in animal models of TBI and is under evaluation in clinical trials. HUCB contains different cell populations but to date, only mesenchymal stem cells have been evaluated for therapy of TBI. Here we present the neurotherapeutic effect, as evaluated by neurological score, using a single dose of HUCB-derived mononuclear cells (MNCs) upon intravenous (IV) administration one day post-trauma in a mouse model of closed head injury (CHI). Delayed (eight days post-trauma) intracerebroventricular administration of MNCs showed improved neurobehavioral deficits thereby extending the therapeutic window for treating TBI. Further, we demonstrated for the first time that HUCB-derived pan-hematopoietic CD45 positive (CD45(+)) cells, isolated by magnetic sorting and characterized by expression of CD45 and CD11b markers (96-99%), improved the neurobehavioral deficits upon IV administration, which persisted for 35 days. The therapeutic effect was in a direct correlation to a reduction in the lesion volume and decreased by pre-treatment of the cells with anti-human-CD45 antibody. At the site of brain injury, 1.5-2 h after transplantation, HUCB-derived cells were identified by near infrared scanning and immunohistochemistry using anti-human-CD45 and anti-human-nuclei antibodies. Nerve growth factor and vascular endothelial growth factor levels were differentially expressed in both ipsilateral and contralateral brain hemispheres, thirty-five days after CHI, measured by enzyme-linked immunosorbent assay. These findings indicate the neurotherapeutic potential of HUCB-derived CD45(+) cell population in a mouse model of TBI and propose their use in the clinical setting of human TBI.
创伤性脑损伤（TBI）的治疗仍是一个未被满足的需求。人脐带血（HUCB）细胞疗法在TBI动物模型中已显示出有前景的结果，并且正在临床试验中进行评估。HUCB包含不同的细胞群体，但迄今为止，仅对间充质干细胞进行了TBI治疗的评估。在此，我们展示了在闭合性颅脑损伤（CHI）小鼠模型中，创伤后一天静脉内（IV）给予单剂量HUCB来源的单核细胞（MNCs）后，通过神经学评分评估的神经治疗效果。延迟（创伤后八天）脑室内给予MNCs显示神经行为缺陷得到改善，从而扩展了治疗TBI的治疗窗口。此外，我们首次证明，通过磁性分选分离并以CD45和CD11b标志物（96 - 99%）表达为特征的HUCB来源的全造血CD45阳性（CD45(+)）细胞，静脉内给药后改善了神经行为缺陷，这种改善持续了35天。治疗效果与损伤体积的减小直接相关，并且用抗人CD45抗体预处理细胞后效果降低。在脑损伤部位，移植后1.5 - 2小时，使用抗人CD45和抗人核抗体通过近红外扫描和免疫组织化学鉴定HUCB来源的细胞。通过酶联免疫吸附测定法测量，在CHI后35天，同侧和对侧脑半球中神经生长因子和血管内皮生长因子水平存在差异表达。这些发现表明HUCB来源的CD45(+)细胞群体在TBI小鼠模型中的神经治疗潜力，并建议将其用于人类TBI的临床治疗。
