Intravenous mesenchymal stem cell therapy for traumatic brain injury.
Intravenous mesenchymal stem cell therapy for traumatic brain injury.
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DOI：
10.3171/2008.9.jns08158
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发表时间：
2009-06
影响因子：
4.1
通讯作者：
Cox CS
中科院分区：
文献类型：
--
作者：
Harting MT;Jimenez F;Xue H;Fischer UM;Baumgartner J;Dash PK;Cox CS
细胞疗法在治疗许多疾病方面已显示出临床前前景，其应用正在转化为临床领域。静脉间充质干细胞（MSC）疗法已被证明可以改善创伤性脑损伤（TBI）后的功能恢复。在此，作者报告了他们重现此类观察结果的尝试，包括 MSC 群体的详细表征、基于非溴脱氧尿苷的细胞标记、宏观和微观细胞追踪、穿过肺微脉管系统的细胞的量化，以及经过充分验证的运动和认知功能恢复测量。对大鼠 MSC 进行分离、体外扩增、免疫表型分析和标记。在接受中度、单侧受控皮质冲击 TBI 后 24 小时，将 400 万个 MSC 静脉注射到 Sprague-Dawley 大鼠体内。使用红外宏观细胞追踪来识别细胞分布。输注后 48 小时和 2 周对脑和肺组织进行的免疫组织化学分析显示这些位置存在移植细胞，并对这些细胞进行了定量。使用动脉内血液采样和流式细胞术来量化到达动脉循环的移植细胞的数量。进行运动和认知行为测试以评估功能恢复。 MSC 输注后 48 小时，大多数细胞定位于肺部。据估计，有 1.5% 至 3.7% 的输注细胞穿过肺部并到达动脉循环，0.295% 到达颈动脉，极少数到达脑实质 (0.0005%) 并留在那里。输注后两周，脑组织中几乎没有发现任何细胞。没有发现恢复过程中运动或认知功能得到改善。间充质干细胞的静脉输注似乎既不会导致细胞显着的急性或长期脑植入，也不会改变运动或认知功能的恢复。不到 4% 的输注细胞可能穿过肺微脉管系统并到达动脉循环，这种现象被称为“肺首过效应”，这可能会限制这种治疗方法的功效。这项研究的数据与之前报告的结果相矛盾，并强调了急性、单剂量、静脉 MSC 疗法治疗 TBI 的潜在缺点。
Cell therapy has shown preclinical promise in the treatment of many diseases, and its application is being translated to the clinical arena. Intravenous mesenchymal stem cell (MSC) therapy has been shown to improve functional recovery after traumatic brain injury (TBI). Herein, the authors report on their attempts to reproduce such observations, including detailed characterizations of the MSC population, non–bromodeoxyuridine-based cell labeling, macroscopic and microscopic cell tracking, quantification of cells traversing the pulmonary microvasculature, and well-validated measurement of motor and cognitive function recovery. Rat MSCs were isolated, expanded in vitro, immunophenotyped, and labeled. Four million MSCs were intravenously infused into Sprague-Dawley rats 24 hours after receiving a moderate, unilateral controlled cortical impact TBI. Infrared macroscopic cell tracking was used to identify cell distribution. Immunohistochemical analysis of brain and lung tissues 48 hours and 2 weeks postinfusion revealed transplanted cells in these locations, and these cells were quantified. Intraarterial blood sampling and flow cytometry were used to quantify the number of transplanted cells reaching the arterial circulation. Motor and cognitive behavioral testing was performed to evaluate functional recovery. At 48 hours post-MSC infusion, the majority of cells were localized to the lungs. Between 1.5 and 3.7% of the infused cells were estimated to traverse the lungs and reach the arterial circulation, 0.295% reached the carotid artery, and a very small percentage reached the cerebral parenchyma (0.0005%) and remained there. Almost no cells were identified in the brain tissue at 2 weeks postinfusion. No motor or cognitive functional improvements in recovery were identified. The intravenous infusion of MSCs appeared neither to result in significant acute or prolonged cerebral engraftment of cells nor to modify the recovery of motor or cognitive function. Less than 4% of the infused cells were likely to traverse the pulmonary microvasculature and reach the arterial circulation, a phenomenon termed the “pulmonary first-pass effect,” which may limit the efficacy of this therapeutic approach. The data in this study contradict the findings of previous reports and highlight the potential shortcomings of acute, single-dose, intravenous MSC therapy for TBI.