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Nature:成纤维细胞转分化成神经元

本期三篇论文介绍了“功能性诱导神经”(iN)细胞由人成纤维细胞的生成,这是一个对再生医学来说非常有希望的过程。

神经元细胞(上图)可由成纤维细胞转分化而来

发现一:Pang等人发现,三个转录因子(分别是Ascl1,亦称Mash1;Brn2,或称 Pou3f2;和Myt1l)的组合能大大增强人胚胎干细胞的神经分化。当与基本的“螺旋-回环-螺旋转录因子” NeuroD1相结合时,这些因子还能将人胎儿和新生儿成纤维细胞转化成iN细胞。

发现二:Caiazzo等人利用三个转录因子组合将出生前及成年的小鼠和人成纤维细胞转化成功能性多巴胺能神经元。这三个转录因子分别是Mash1、 Nurr1 (或Nr4a2) 和 Lmx1a。转化是直接进行的,不用退分化成干细胞,而且这种转化在来自帕金森氏症患者及来自健康供者的细胞中都能发生。

发现三:Yoo等人采用了另外一种方法。他们发现,miRNA在神经分化决定中有一个指导性作用。miR-9/9* 和 miR-124的表达能诱导人成纤维细胞直接转化功能性神经元,而增添一些神经元转录因子可以帮助这一过程的进行。

 

英文摘要

Induction of human neuronal cells by defined transcription factors

Somatic cell nuclear transfer, cell fusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diverse somatic cell types. We recently observed that forced expression of a combination of three transcription factors, Brn2 (also known as Pou3f2), Ascl1 and Myt1l, can efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells. Here we show that the same three factors can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with the basic helix–loop–helix transcription factor NeuroD1, these factors could also convert fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human iN cells were able to generate action potentials and many matured to receive synaptic contacts when co-cultured with primary mouse cortical neurons. Our data demonstrate that non-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors. These methods may facilitate robust generation of patient-specific human neurons for in vitro disease modelling or future applications in regenerative medicine.

 

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成纤维细胞 神经元
 
 
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