Department of Neural Repair and Therapeutics, Sapporo Medical University, South-1st, West-16th, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.
Brain. 2011 Jun;134(Pt 6):1790-807. doi: 10.1093/brain/awr063. Epub 2011 Apr 14.
Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36-133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.
人骨髓间充质干细胞移植已被证明可减少动物中风模型的梗死面积并改善功能预后。在此，我们报告了一项评估在中风患者中移植自体扩增人骨髓间充质干细胞的可行性和安全性的研究。我们报告了一项针对 12 名缺血性灰质、白质和混合病变患者的非盲研究，与之前一项针对在胎牛血清中扩增的自体间充质干细胞的研究相比，后者主要关注灰质病变。在人血清中培养的细胞比在胎牛血清中更快地扩增，从而缩短了细胞制备时间，并降低了传播性疾病（如牛海绵状脑病）的风险。自体骨髓间充质干细胞在中风后 36-133 天静脉输注。所有患者均行磁共振血管造影以识别血管病变，并在细胞输注前和 1 年后的不同时间进行磁共振成像。在一些患者中进行了磁共振灌注成像和 3D 追踪。使用国立卫生研究院中风量表和改良 Rankin 评分对神经状态进行评分。我们未观察到任何中枢神经系统肿瘤、异常细胞生长或神经恶化，并且在任何患者中均未发现静脉血栓栓塞、全身恶性肿瘤或全身感染。与输注前相比，在输注后第 1 天至第 1 周期间，每日国立卫生研究院中风量表变化的中位数为 0.36。在更长的输注后间隔内，每日国立卫生研究院中风量表评分的变化率也更接近初始评分和细胞输注之间的间隔，也显示出输注后增加。细胞输注后 1 周时，磁共振成像评估的平均病变体积减少了>20%。尽管我们要强调的是，当前的研究是不设盲的，未评估整体功能或不同类型缺陷的相对重要性，也不能排除安慰剂效应或中风自然史导致的恢复的贡献，但我们的观察结果为在中风患者中输注相对大剂量的自体扩增人骨髓间充质干细胞提供了可行性和安全性的证据，并支持需要进行更多的、盲法、安慰剂对照研究来评估自体间充质人干细胞输注治疗中风的效果。
