Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming
Rapid Conversion of Fibroblasts into Functional Forebrain GABAergic Interneurons by Direct Genetic Reprogramming
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DOI：
10.1016/j.stem.2015.09.002
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发表时间：
2015-12-03
期刊：
影响因子：
23.9
通讯作者：
Broccoli, Vania
中科院分区：
文献类型：
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作者：
Colasante, Gaia;Lignani, Gabriele;Broccoli, Vania
GABA能中间神经元（IN）的移植可以在癫痫和其他神经系统疾病的动物模型中提供长期的功能益处。而GABA能IN可以从胚胎干细胞中分化出来，GABA能IN的替代来源可能更容易用于疾病建模和移植。我们确定了五个因子（Foxg 1，Sox 2，Ascl 1，Dlx 5和Lhx 6），将小鼠成纤维细胞转化为诱导GABA能INs（iGABA-INs）具有端脑INs. Factor过表达激活GABA能命运特化所需的转录网络的分子特征。iGABA-IN显示出与皮质IN相当的逐渐成熟的放电模式，形成功能性突触，并释放GABA。重要的是，iGABA-IN在移植到小鼠海马体中后存活并成熟。光遗传学刺激证明了移植的iGABA-IN功能性整合到宿主电路中，触发宿主颗粒神经元活性的抑制。这五个因素还将人类细胞转化为功能性GABA能IN。这些特性表明iGABA-IN具有疾病建模和基于细胞的神经系统疾病治疗方法的潜力。
Transplantation of GABAergic interneurons (INs) can provide long-term functional benefits in animal models of epilepsy and other neurological disorders. Whereas GABAergic INs can be differentiated from embryonic stem cells, alternative sources of GABAergic INs may be more tractable for disease modeling and transplantation. We identified five factors (Foxg1, Sox2, Ascl1, Dlx5, and Lhx6) that convert mouse fibroblasts into induced GABAergic INs (iGABA-INs) possessing molecular signatures of telencephalic INs. Factor overexpression activates transcriptional networks required for GABAergic fate specification. iGABA-INs display progressively maturing firing patterns comparable to cortical INs, form functional synapses, and release GABA. Importantly, iGABA-INs survive and mature upon being grafted into mouse hippocampus. Optogenetic stimulation demonstrated functional integration of grafted iGABA-INs into host circuitry, triggering inhibition of host granule neuron activity. These five factors also converted human cells into functional GABAergic INs. These properties suggest that iGABA-INs have potential for disease modeling and cell-based therapeutic approaches to neurological disorders.