Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats
Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats
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DOI：
10.1093/brain/awl261
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发表时间：
2006-12-01
期刊：
影响因子：
14.5
通讯作者：
Dihne, Marcel
中科院分区：
文献类型：
--
作者：
Buehnemann, Claudia;Scholz, Andreas;Dihne, Marcel
中风是西方国家死亡和残疾的主要原因之一，但尽管进行了大量研究，但治疗中风相关脑组织梗死的选择很少。在实验性中风中，细胞疗法可以部分逆转一些行为缺陷。然而，潜在的机制仍然是未知的，因为大多数研究显示，只有很少的，如果有的话，神经元替代的证据和观察到的行为改善似乎是相关的，而不是移植物衍生的诱导剩余的宿主组织中的阳性反应，而不是细胞替代移植本身。本研究旨在测试内皮素诱导的大脑中动脉闭塞大鼠中基于小鼠胚胎干细胞（ESC）的方法。将胚胎干细胞衍生的神经前体细胞移植到成年大鼠的梗死核心和外周后，测试了细胞疗法关于移植物存活、神经元产量和多样性以及移植细胞的电生理特征的功效。在这里，我们表明，移植的细胞可以生存，虽然不完全，最有可能是由于一个持续的免疫反应，在梗死核心长达12周的移植后，他们分化成化学成熟的胶质细胞和神经元的不同的神经递质亚型高产。最重要的是，移植细胞表现出电生理功能神经元的特征，具有电压门控钠电流，使这些细胞能够激发动作电位。此外，在移植后的前7周，我们观察到自发的兴奋性突触后电流的移植衍生细胞表明突触输入。因此，我们的观察表明，基于ESC的再生方法在急性坏死的细胞环境中可能是成功的。
Stroke represents one of the leading causes of death and disability in Western countries, but despite intense research, only few options exist for the treatment of stroke-related infarction of brain tissue. In experimental stroke, cell therapy can partly reverse some behavioural deficits. However, the underlying mechanisms have remained unknown as most studies revealed only little, if any, evidence for neuronal replacement and the observed behavioural improvements appeared to be related rather to a graft-derived induction of a positive response in the remaining host tissue than to cell replacement by the graft itself. The present study was performed to test a murine embryonic stem cell (ESC)-based approach in rats subjected to endothelin-induced middle cerebral artery occlusion. Efficacy of cell therapy regarding graft survival, neuronal yield and diversity, and electrophysiological features of the grafted cells were tested after transplanting ESC-derived neural precursors into the infarct core and periphery of adult rats. Here, we show that grafted cells can survive, albeit not entirely, most probably as a consequence of an ongoing immune response, within the infarct core for up to 12 weeks after transplantation and that they differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. Most importantly, transplanted cells demonstrate characteristics of electrophysiologically functional neurons with voltage-gated sodium currents that enable these cells to fire action potentials. Additionally, during the first 7 weeks after transplantation we observed spontaneous excitatory post-synaptic currents in graft-derived cells indicating synaptic input. Thus, our observations show that ESC-based regenerative approaches may be successful in an acutely necrotic cellular environment.