Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
Brain Repair Group, Neuroscience and Mental Health Research Institute, School of Bioscience, Cardiff University, Cardiff CF10 3AX, UK.
Development. 2015 Apr 1;142(7):1375-86. doi: 10.1242/dev.117093.
The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells.
从人类胚胎干细胞（hESCs）和诱导多能干细胞（hiPSCs）中高效产生纹状体神经元对于实现它们在疾病建模、药物筛选和亨廷顿病细胞治疗中的应用具有重要意义。GABA 能中型棘突神经元（MSNs）是纹状体的主要投射神经元，并且在亨廷顿病的早期阶段特异性退化。在这里，我们报告说激活素 A 以一种不依赖于 sonic hedgehog 的方式诱导源自 hESCs 和 hiPSCs 的新生神经祖细胞中出现外侧神经节隆起（LGE）特征。纹状体表型的正确特化进一步通过诱导纹状体转录因子 CTIP2、GSX2 和 FOXP2 来证明。至关重要的是，这些人类 LGE 祖细胞在培养物中以及在亨廷顿病大鼠模型中成年纹状体中的移植后，很容易分化为表达纹状体投射神经元标志物 DARPP32 的有丝分裂后神经元。激活素诱导的神经元在体外也表现出适当的纹状体样电生理学特性。总之，我们的研究结果表明了一种从人类多能干细胞中高效分化 GABA 能纹状体 MSNs 的新途径。
