New approaches for direct conversion of patient fibroblasts into neural cells.
New approaches for direct conversion of patient fibroblasts into neural cells.
复制标题
DOI：
10.1016/j.brainres.2015.10.012
复制
发表时间：
2017-02-01
期刊：
影响因子：
2.9
通讯作者：
Ichida JK
中科院分区：
文献类型：
--
作者：
Gopalakrishnan S;Hor P;Ichida JK
最近具有里程碑意义的研究表明，通过两种不同的方法产生与疾病相关的人类细胞类型;使用外部形态发生剂的干细胞分化或使用遗传因子的谱系转换。定向分化通过在体外环境中提供发育线索将胚胎干细胞（ESC）或诱导多能干细胞（iPSC）改变为所需的细胞类型。直接重编程通过引入外源谱系特异性转录因子来实现，以将任何体细胞类型转化为另一种，从而绕过中间多能阶段。多种体细胞类型如血液、角质形成细胞和成纤维细胞可用于衍生iPSC细胞。然而，该过程是耗时、费力、昂贵的，并且甚至在来自同一患者的不同iPSC系之间产生具有报告的表观遗传异质性的细胞，其可以传播表型变异性。使用多能细胞作为细胞替代疗法的起始材料的主要问题是它们的不完全分化和它们在移植后形成肿瘤的倾向。相比之下，转录因子介导的重编程提供了一种直接的靶细胞类型的途径。这可以允许在给定的时间快速比较大的患者和对照样本队列，以进行疾病建模。此外，驱动成熟的转录因子可以产生比定向分化更多的功能成熟细胞。几项研究已经证明了从成纤维细胞产生细胞类型如心肌细胞、肝细胞和神经元的可行性。在这里，我们将讨论关于体细胞类型直接重编程为不同神经细胞的最新进展和关键挑战。
Recent landmark studies have demonstrated the production of disease-relevant human cell types by two different methods; differentiation of stem cells using external morphogens or lineage conversion using genetic factors. Directed differentiation changes embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) into a desired cell type by providing developmental cues in an in vitro environment. Direct reprogramming is achieved by the introduction of exogenous lineage specific transcription factors to convert any somatic cell type into another, thereby bypassing an intermediate pluripotent stage. A variety of somatic cell types such as blood, keratinocytes and fibroblasts can be used to derive iPSC cells. However, the process is time consuming, laborious, expensive and gives rise to cells with reported epigenetic heterogeneity even amongst different iPSC lines from same patient which could propagate phenotypic variability. A major concern with the use of pluripotent cells as starting material for cell replacement therapy is their incomplete differentiation and their propensity to form tumors following transplantation. In comparison, transcription factor mediated reprogramming offers a direct route to target cell types. This could allow for rapid comparison of large cohorts of patient and control samples at a given time for disease modeling. Additionally, transcription factors that drive maturation may yield more functionally mature cells than directed differentiation. Several studies have demonstrated the feasibility of generating of cell types such as cardiomyocytes, hepatocytes, and neurons from fibroblasts. Here, we will discuss recent advances and key challenges regarding direct reprogramming of somatic cell types into diverse neural cells.