Neural induction with Neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain
Neural induction with Neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain
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DOI：
10.1634/stemcells.2008-0108
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发表时间：
2008-09-01
期刊：
影响因子：
5.2
通讯作者：
Suh-Kim, Haeyoung
中科院分区：
文献类型：
--
作者：
Kim, Sung-Soo;Yoo, Seung-Wan;Suh-Kim, Haeyoung
间充质干细胞（MSC）已被证明可以改善各种神经功能障碍。这种效应被认为是由它们的旁分泌功能介导的，因为这些细胞很少分化成神经元细胞。MSC的神经诱导是否有益于神经系统疾病的替代治疗是临床感兴趣的。在这里，我们报告说，神经生成素1（Ngn 1），一个proneural基因，指导神经元分化的祖细胞在发展过程中，是足以转换成神经元的MSC中胚层细胞的命运。Ngn1表达MSC表达神经元特异性蛋白，包括NeuroD和电压门控Ca2+和Na+通道，这些在亲本MSC中不存在。最重要的是，与亲本MSC相比，在动物中风模型中移植表达Ngn 1的MSC显著改善了运动功能。具有Ngn 1的MSC在缺血性脑中聚集，在那里它们表达成熟的神经元标记物，包括微管相关蛋白2、神经丝200和囊泡谷氨酸转运蛋白2，并且在功能上连接到宿主神经元。在减少Iba 1（+）、ED 1（+）炎性细胞和末端脱氧核苷酸转移酶dUTP缺口末端标记（+）凋亡细胞的数量以及增加增殖的Ki 67（+）细胞的数量方面，有和没有Ngn 1的MSC没有区别。数据表明，除了MSC的内在旁分泌功能外，能够转分化为神经元细胞的MSC还显著改善了运动功能障碍。因此，MSC的神经诱导对于治疗神经功能障碍是有利的。
Mesenchymal stem cells (MSCs) have been shown to ameliorate a variety of neurological dysfunctions. This effect is believed to be mediated by their paracrine functions, since these cells rarely differentiate into neuronal cells. It is of clinical interest whether neural induction of MSCs is beneficial for the replacement therapy of neurological diseases. Here we report that expression of Neurogenin1 (Ngn1), a proneural gene that directs neuronal differentiation of progenitor cells during development, is sufficient to convert the mesodermal cell fate of MSCs into a neuronal one. Ngn1-expressing MSCs expressed neuron-specific proteins, including NeuroD and voltage-gated Ca2+ and Na+ channels that were absent in parental MSCs. Most importantly, transplantation of Ngn1-expressing MSCs in the animal stroke model dramatically improved motor functions compared with the parental MSCs. MSCs with Ngn1 populated the ischemic brain, where they expressed mature neuronal markers, including microtubule associated protein 2, neurofilament 200, and vesicular glutamate transporter 2, and functionally connected to host neurons. MSCs with and without Ngn1 were indistinguishable in reducing the numbers of Iba1(+), ED1(+) inflammatory cells, and terminal deoxynucleotidyl transferase dUTP nick-end labeling(+) apoptotic cells and in increasing the numbers of proliferating Ki67(+) cells. The data indicate that in addition to the intrinsic paracrine functions of MSCs, motor dysfunctions were remarkably improved by MSCs able to transdifferentiate into neuronal cells. Thus, neural induction of MSCs is advantageous for the treatment of neurological dysfunctions.