Conversion of Fibroblasts to fxnal Spinal Motor Neurons Using Defined Factor

摘要 哺乳动物的神经系统由许多不同的神经元亚型组成，每种亚型都有 其自身的表型和对退行性疾病的区分敏感性。尽管某些特定的神经元类型 可以从完整的啮齿动物胚胎中分离出来，或者从干细胞中进行工程，用于翻译研究，这些 方法是耗时的，许多神经元亚型是无法接触到的。转录因子介导的 重新编程可能提供一条更直接的途径来产生神经元，用于疾病建模和 再生医学，但目前尚不清楚这种方法是否可以用于创造具有翻译能力的细胞 实用程序。在这里，我们建议确定一组足以将成纤维细胞转化为 功能性脊髓运动神经元。我们将描述重新编程过程的特征并检查分子 以及由此产生的运动神经元的功能特性，以确定它们的治疗潜力。 这些研究将为研究患者特有的运动神经元提供一个可获得的来源 神经退行性疾病，表明特定的成体细胞类型可以直接从体细胞产生 使用定义因子的单元格，并机械地剖析定义因子重新编程过程。

Abstract The mammalian nervous system is composed of a multitude of distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although some specific neuronal types can be isolated from intact rodent embryos or engineered from stem cells for translational studies, these approaches are time-consuming and many neuronal subtypes are inaccessible. Transcription factor-mediated reprogramming might provide a more direct route to the generation of neurons for disease modeling and regenerative medicine, but it is currently unclear if this approach can be used to create cells with translational utility. Here, we propose to identify a set of transcription factors sufficient to convert fibroblasts into functional spinal motor neurons. We will characterize the reprogramming process and examine the molecular and functional properties of the resulting motor neurons in order to determine their therapeutic potential. These studies will provide an accessible source of patient-specific motor neurons for the study of neurodegenerative disease, demonstrate that specific adult cell types can be directly generated from somatic cells using defined factors, and mechanistically dissect the defined-factor reprogramming process.