Generation of induced neuronal cells by the single reprogramming factor ASCL1.
Generation of induced neuronal cells by the single reprogramming factor ASCL1.
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DOI：
10.1016/j.stemcr.2014.05.020
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发表时间：
2014-08-12
影响因子：
5.9
通讯作者：
Wernig, Marius
中科院分区：
文献类型：
--
作者：
Chanda, Soham;Ang, Cheen Euong;Davila, Jonathan;Pak, ChangHui;Mall, Moritz;Lee, Qian Yi;Ahlenius, Henrik;Jung, Seung Woo;Suedhof, Thomas C.;Wernig, Marius
将非神经细胞直接转化为功能神经元，为神经疾病建模和再生医学带来了巨大的希望。我们之前报道了通过强制表达三种转录因子：ASCL1、Myt1和Brn2，将小鼠胚胎成纤维细胞(MEF)快速重编程为成熟的诱导神经元(IN)细胞。在这里，我们证明了仅ASCL1就足以从小鼠和人类成纤维细胞和胚胎干细胞产生具有功能的In细胞，表明ASCL1是不同细胞环境中In细胞重编程的关键驱动因素，Myt1l和Brn2的作用主要是促进神经元的成熟过程。ASCL1诱导的单因素神经元(1F-In)表达成熟的神经元标志物，表现出典型的被动和主动的固有膜特性，并形成功能性突触前和突触后结构。令人惊讶的是，ASCL1诱导的细胞主要是兴奋性的，这表明ASCL1是允许的，但单独不是抑制性神经元谱系的决定性因素。ASCL1单独从成纤维细胞和胚胎干细胞产生功能神经元，ASCL1诱导的1F-in细胞表现出缓慢的成熟动力学ASCL1过度表达诱导内源性Myt1l和Brn2 ASCL1诱导的1F-in细胞主要是兴奋性的直接将非神经元细胞重编程为功能神经元通常被认为需要多种转录因子的过度表达，但它们的功能层次尚不清楚。在这里，Wernig和Südhof及其同事展示了过表达一种“靶向”先锋因子ASCL1，足以从小鼠和人类来源的成纤维细胞和胚胎干细胞中产生诱导神经细胞。
Direct conversion of nonneural cells to functional neurons holds great promise for neurological disease modeling and regenerative medicine. We previously reported rapid reprogramming of mouse embryonic fibroblasts (MEFs) into mature induced neuronal (iN) cells by forced expression of three transcription factors: ASCL1, MYT1L, and BRN2. Here, we show that ASCL1 alone is sufficient to generate functional iN cells from mouse and human fibroblasts and embryonic stem cells, indicating that ASCL1 is the key driver of iN cell reprogramming in different cell contexts and that the role of MYT1L and BRN2 is primarily to enhance the neuronal maturation process. ASCL1-induced single-factor neurons (1F-iN) expressed mature neuronal markers, exhibited typical passive and active intrinsic membrane properties, and formed functional pre- and postsynaptic structures. Surprisingly, ASCL1-induced iN cells were predominantly excitatory, demonstrating that ASCL1 is permissive but alone not deterministic for the inhibitory neuronal lineage. ASCL1 alone generates functional neurons from fibroblast and embryonic stem cells ASCL1-induced 1F-iN cells display slow maturation kinetics ASCL1 overexpression induces endogenous expression of Myt1l and Brn2 ASCL1-induced 1F-iN cells are predominantly excitatory Direct reprogramming of nonneuronal cells into functional neurons is often considered to require overexpression of multiple transcription factors, but their functional hierarchy remained unknown. Here, Wernig, Südhof, and colleagues show that overexpression of an “on target” pioneer factor, ASCL1, is sufficient to generate induced neuronal cells from fibroblast and embryonic stem cells of both mouse and human origin.
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影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
通过确定的因素将成纤维细胞直接转化为功能性神经元。
影响因子：
64.8
作者：
Vierbuchen, Thomas;Ostermeier, Austin;Pang, Zhiping P.;Kokubu, Yuko;Suedhof, Thomas C.;Wernig, Marius
通讯作者：
Wernig, Marius
影响因子：
64.5
作者：
Wapinski OL;Vierbuchen T;Qu K;Lee QY;Chanda S;Fuentes DR;Giresi PG;Ng YH;Marro S;Neff NF;Drechsel D;Martynoga B;Castro DS;Webb AE;Südhof TC;Brunet A;Guillemot F;Chang HY;Wernig M
通讯作者：
Wernig M
影响因子：
3.9
作者：
Sugimoto, Yasutaka;Furuno, Tadahide;Nakanishi, Mamoru
通讯作者：
Nakanishi, Mamoru
DOI：
10.1073/pnas.1316240110
发表时间：
2013-10-08
影响因子：
11.1
作者：
Chanda, Soham;Marro, Samuele;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.