Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse.
Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse.
复制标题
评估鼻内间充质干细胞治疗小鼠新生儿脑损伤的长期安全性和功效。
DOI：
10.1038/pr.2015.145
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发表时间：
2015-11
影响因子：
3.6
通讯作者：
Heijnen CJ
中科院分区：
文献类型：
--
作者：
Donega V;Nijboer CH;van Velthoven CT;Youssef SA;de Bruin A;van Bel F;Kavelaars A;Heijnen CJ
对于临床转化，我们评估了缺氧缺血（HI）后鼻内间充质干细胞（MSC）治疗是否在14个月时诱导脑或外周肿瘤形成。此外，确定了MSC对行为和病变大小的长期影响。在9日龄小鼠中诱导HI。在HI后10 d，幼仔接受0.5 × 106 MSC或溶剂的鼻内给药。对每只小鼠的39个器官进行了全面的宏观和显微病理学分析。在10 d、28 d、6 mo和9 mo时，在圆筒直立试验中评估感觉运动行为。在HI后3个月和14个月，用新物体识别测试测量认知。在5周和14个月时，通过分析小鼠抗微管相关蛋白2（MAP 2）和小鼠抗髓鞘碱性蛋白（MBP）染色来确定病变大小。在HI后14个月，我们在用MSC治疗的HI小鼠的鼻甲、脑或其他器官中没有观察到任何瘤形成。此外，我们的研究结果表明，MSC诱导的感觉运动和认知功能的改善是持久的。相比之下，HI-媒介物小鼠显示出严重的行为障碍。MAP 2和MBP阳性区域的恢复持续到MSC治疗后14个月。我们的研究结果提供了强有力的证据，长期安全性和MSC治疗后，新生儿HI小鼠的积极作用。
For clinical translation, we assessed whether intranasal mesenchymal stem cell (MSC) treatment after hypoxia–ischemia (HI) induces neoplasia in the brain or periphery at 14 mo. Furthermore, the long-term effects of MSCs on behavior and lesion size were determined. HI was induced in 9-d-old mice. Pups received an intranasal administration of 0.5 × 106 MSCs or vehicle at 10 d post-HI. Full macroscopical and microscopical pathological analysis of 39 organs per mouse was performed. Sensorimotor behavior was assessed in the cylinder-rearing test at 10 d, 28 d, 6 mo, and 9 mo. Cognition was measured with the novel object recognition test at 3 and 14 mo post-HI. Lesion size was determined by analyzing mouse-anti-microtubule-associated protein 2 (MAP2) and mouse-anti-myelin basic protein (MBP) staining at 5 wk and 14 mo. At 14 mo post-HI, we did not observe any neoplasia in the nasal turbinates, brain, or other organs of HI mice treated with MSCs. Furthermore, our results show that MSC-induced improvement of sensorimotor and cognitive function is long lasting. In contrast, HI-vehicle mice showed severe behavioral impairment. Recovery of MAP2- and MBP-positive area lasted up to 14 mo following MSC treatment. Our results provide strong evidence of the long-term safety and positive effects of MSC treatment following neonatal HI in mice.