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Direct induction of functional neuronal cells from fibroblast-like cells derived from adult human retina - ScienceDirect

机译:从成年人类视网膜衍生的成纤维细胞样细胞直接诱导功能神经元细胞-ScienceDirect

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Obtaining and manipulating neuronal cells are critical for neural biology basic mechanism studies and translational applications. Recent advances in protocol development and mechanism dissections have made direct induction of neuronal cells from other somatic cells (iN) a promising strategy for such purposes. In this study, we established a protocol to expand a population of fibroblast-like cells from adult human retinal tissues, which can be reprogrammed into iNs by forced expression of neurogenic transcription factors. Interestingly, the combination of Ascl1, Brn2, Myt1l, and NeuroD1 transcription factors, which has been demonstrated to be sufficient to reprogram human embryonic and dermal fibroblasts into iNs, failed to reprogram the fibroblast-like cells from human retinas into iNs. Instead, supplementing Ascl1 with Pax6 sufficed to convert the cells into iNs, which exhibited a typical neuronal morphology, expressed neural marker genes, displayed active and passive neuronal membrane activities, and made synaptic communications with other neurons. Moreover, iNs converted from retina-derived fibroblast-like cells contained high ratios of γ-Aminobutyric acid- (GABA-) and tyrosine hydroxylase- (TH-) positive neurons. Thus, the present study proposes a protocol that makes use of discarded retinal tissues from eye banks for iN generation, and suggests that different sources of somatic cells require different iN induction recipes and may also affect the iN subtype outputs. Our study may also facilitate the future development of methods to convert resident cells in situ into retinal neurons for treating retinal degeneration disease purpose.
机译:获取和操纵神经元细胞对于神经生物学基本机制研究和转化应用至关重要。协议开发和机制解剖的最新进展已使从其他体细胞(iN)直接诱导神经元细胞成为实现此类目的的有前途的策略。在这项研究中,我们建立了从成人视网膜组织中扩增成纤维细胞样细胞群体的协议,可以通过强制表达神经源性转录因子将其重新编程为iNs。有趣的是,已被证明足以将人类胚胎和真皮成纤维细胞重编程为iNs的Ascl1,Brn2,Myt11和NeuroD1转录因子的组合未能将人类视网膜中的成纤维细胞样细胞重编程为iNs。取而代之的是,用Pax6补充Ascl1足以将细胞转化为iNs,后者表现出典型的神经元形态,表达神经标记基因,显示主动和被动神经元膜活性,并与其他神经元进行突触通讯。此外,从视网膜来源的成纤维细胞样细胞转化的iNs含有高比例的γ-氨基丁酸-(GABA-)和酪氨酸羟化酶-(TH-)阳性神经元。因此,本研究提出了一种协议,该协议利用眼库中废弃的视网膜组织进行iN生成,并建议不同来源的体细胞需要不同的iN诱导配方,并且还可能影响iN亚型的输出。我们的研究还可能促进将来将驻留细胞原位转化为视网膜神经元以治疗视网膜变性疾病的方法的发展。

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