Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model.
Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model.
复制标题
人缪斯细胞在亚急性lacunar streos模型中重建神经元电路。
DOI：
10.1161/strokeaha.116.014950
复制
发表时间：
2017-02
期刊：
影响因子：
8.3
通讯作者：
Dezawa M
中科院分区：
文献类型：
--
作者：
Uchida H;Niizuma K;Kushida Y;Wakao S;Tominaga T;Borlongan CV;Dezawa M
MUSE细胞是一种内源性非致瘤干细胞，具有多潜能，可从培养的骨髓间充质干细胞(MSCs)中获得SSEA-3+细胞。在移植到神经系统疾病模型后，缪斯细胞发挥修复作用，但确切的机制仍不确定。在免疫缺陷小鼠腔隙性脑梗塞后两周，我们通过将血清/无异种培养的人BM-MUSE细胞移植到病变周围脑内进行了基于机制的实验。最初移植的MUSE细胞中约有28%在8周后仍留在宿主脑内，并自发分化为表达NeuN(~62%)、MAP2(~30%)和GST-pi(~12%)的细胞。葡聚糖追踪显示宿主神经元与受损运动皮质和前角的缪斯细胞之间存在联系。小鼠细胞通过同侧锥体束伸入神经突起，与对侧交叉，到达脊髓背索的锥体束。移植缪斯的中风小鼠在柱状试验中表现出显著的恢复，这是由人类选择性白喉毒素逆转的。在移植后10个月，只在大脑中检测到人类特定的Alu序列，而在其他器官中没有检测到，没有肿瘤形成的证据。延迟亚急性期的移植显示MUSE细胞分化为神经细胞，促进了神经重建，改善了功能，并在延长的移植物成熟期显示了坚实的安全结果，表明其治疗腔隙卒中的潜力。
Muse cells are endogenous non-tumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3+ cells from the bone marrow (BM) from cultured BM-mesenchymal stem cells (MSCs). After transplantation into neurological disease models, Muse cells exert repair effects, but the exact mechanism remains inconclusive. We conducted mechanism-based experiments by transplanting serum/xeno-free cultured-human BM-Muse cells into the peri-lesion brain at two weeks after lacunar infarction in immunodeficient mice. Approximately 28% of initially transplanted Muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (~62%), MAP2 (~30%), and GST-pi (~12%). Dextran tracing revealed connections between host neurons and Muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse-transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post-transplantation, human specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation. Transplantation at the delayed subacute phase showed Muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.