Direct induction of neural progenitor cells transiently passes through a partially reprogrammed state
Direct induction of neural progenitor cells transiently passes through a partially reprogrammed state
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直接诱导神经祖细胞短暂地经历部分重编程状态
DOI：
10.1016/j.biomaterials.2016.12.007
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发表时间：
2017-03-01
期刊：
影响因子：
14
通讯作者：
Gao, Shaorong
中科院分区：
文献类型：
--
作者：
Gao, Rui;Xiu, Wenchao;Gao, Shaorong
功能性神经前体细胞（NPC）的产生为神经退行性疾病的研究和临床应用带来了巨大的希望。传统上，NPC来源于胚胎干细胞（ESC）和诱导多能干细胞（iPSC），或者NPC可以通过转录因子组或通过化学混合物和/或缺氧的组合从体细胞直接转化。然而，胚胎干细胞的伦理问题、诱导性多能干细胞的肿瘤发生风险、外源基因的转基因整合以及化学诱导的核周细胞（chemical induced npc，ciNPCs）的操作复杂和耗时等问题限制了这些策略的应用。在这里，我们描述了一种通过使用诱导和/或允许信号传导培养条件从小鼠胚胎和成体成纤维细胞产生生长因子诱导的神经祖细胞（giNPC）的新方法。这些giNPC在转录网络和神经谱系分化潜力方面与脑源性NPC非常相似。此外，这种体细胞到NPC的诱导是一个渐进的过程，包括起始、中间、成熟和稳定阶段。重要的是，基因表达和组蛋白修饰分析进一步表明在诱导NPC的产生过程中存在部分重编程状态，其中谱系特异性基因和多能性相关基因被瞬时激活。因此，我们的研究描述了在无转基因直接诱导策略中也存在的潜在安全性问题，并强调了从将来的临床试验中产生的NPC中排除残留部分重编程和/或畸胎瘤样细胞的可能性的重要性。(C)2016爱思唯尔有限公司版权所有
The generation of functional neural progenitor cells (NPCs) holds great promise for both research and clinical applications in neurodegenerative diseases. Traditionally, NPCs are derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or NPCs can be directly converted from somatic cells by sets of transcription factors or by a combination of chemical cocktails and/or hypoxia. However, the ethical issues of ESCs, the risk of tumorigenesis from iPSCs and transgenic integration from exogenous genes as well as complicated manipulation and time-consuming of chemical induced NPCs (ciNPCs) limit the applications of these strategies. Here, we describe a novel method for generating growth factor induced neural progenitor cells (giNPCs) from mouse embryonic and adult fibroblasts by using inductive and/or permissive signaling culture conditions. These giNPCs closely resemble brain-derived NPCs in terms of transcription networks and neural lineage differentiation potentials. Moreover, this somatic cell to NPC induction is a gradual process that includes initiation, intermediate, maturation and stabilization stages. Importantly, gene expression and histone modification analyses further indicate a partially reprogrammed state during the generation process of induced NPCs, in which lineage specific genes and pluripotency associated genes are transiently activated. Our study therefore describes the potential safety problems that also exist in the transgene-free direct induction strategy and highlights the importance of excluding the possibility of residual partially reprogrammed and/or teratoma-like cells from the generated NPCs for future clinical trials. (C) 2016 Elsevier Ltd. All rights reserved.