Kevin Eggan2014-02-27 12:27 PM

将小鼠和人类纤维细胞转化为功能性脊髓运动神经元。 Conversion of mouse and human fibroblasts into functional spinal motor neurons.

论文摘要

哺乳动物神经系统包括了许多不同神经元亚型,每个亚型对退行性疾病都具有特定表型和不同灵敏度。虽然用于转译研究的具体神经元类型可通过隔离啮齿类动物胚胎或改造干细胞而获得, 但转录因子介导的重编程可能会为子代提供更直接的路径。我们在此表示,选择转录因子的强制表达足以将小鼠和人类纤维细胞转变成诱发性运动神经元(iMNs)。iMNs展现了形态,基因表达标记,电生理学,突触功能,体内植入能力和对类似胚胎源性运动神经元的退化性刺激的灵敏度。我们表明,转化的成纤维细胞并不以增殖性神经前体细胞态来通过并因此通过不同于胚胎发育的路径来形成真正的运动神经元。我们的研究结果表明成纤维细胞可以直接转换成特定的分化和功能性神经亚型,即脊髓运动神经元。


Abstract

The mammalian nervous system comprises many distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although specific neuronal types can be isolated from rodent embryos or engineered from stem cells for translational studies, transcription factor-mediated reprogramming might provide a more direct route to their generation. Here we report that the forced expression of select transcription factors is sufficient to convert mouse and human fibroblasts into induced motor neurons (iMNs). iMNs displayed a morphology, gene expression signature, electrophysiology, synaptic functionality, in vivo engraftment capacity, and sensitivity to degenerative stimuli similar to those of embryo-derived motor neurons. We show that the converting fibroblasts do not transit through a proliferative neural progenitor state, and thus form bona fide motor neurons via a route distinct from embryonic development. Our findings demonstrate that fibroblasts can be converted directly into a specific differentiated and functional neural subtype, the spinal motor neuron.

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Kevin Eggan

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