Comparison of three congruent patient-specific cell types for the modelling of a human genetic Schwann-cell disorder
Comparison of three congruent patient-specific cell types for the modelling of a human genetic Schwann-cell disorder
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DOI：
10.1038/s41551-019-0381-8
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发表时间：
2019-07-01
影响因子：
28.1
通讯作者：
Lee, Gabsang
中科院分区：
文献类型：
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作者：
Mukherjee-Clavin, Bipasha;Mi, Ruifa;Lee, Gabsang
患者特异性人诱导多能干细胞（hipsc）在遗传疾病建模方面具有很大的前景。然而，这些细胞在基因表达方面表现出广泛的个体内和个体间差异，这使得区分真阳性和假阳性表型具有挑战性。来自hiPSC表型和携带相同疾病突变的人胚胎干细胞（hESCs）的数据也缺乏。在这里，我们报告了三种一致的患者特异性细胞类型的分子，细胞和功能特征的比较- hipsc， hESCs和直接谱系转化细胞-来源于目前可用的分化和直接重编程技术，用于模拟charcot - mary - tooth 1A，一种人类遗传性薛旺细胞疾病，具有1.4 Mb染色体重复。我们发现趋化因子C-X-C基序配体趋化因子-1 （CXCL1）和巨噬细胞趋化蛋白-1 （MCP1）在所有三种一致的模型和临床患者样本中普遍上调。使用来自普通患者的体细胞的单一遗传疾病的一致模型的发展将有助于寻找趋同表型。
Patient-specific human-induced pluripotent stem cells (hiPSCs) hold great promise for the modelling of genetic disorders. However, these cells display wide intra-and interindividual variations in gene expression, which makes distinguishing true-positive and false-positive phenotypes challenging. Data from hiPSC phenotypes and human embryonic stem cells (hESCs) harbouring the same disease mutation are also lacking. Here, we report a comparison of the molecular, cellular and functional characteristics of three congruent patient-specific cell types-hiPSCs, hESCs and direct-lineage-converted cells-derived from currently available differentiation and direct-reprogramming technologies for use in the modelling of Charcot-Marie-Tooth 1A, a human genetic Schwann-cell disorder featuring a 1.4 Mb chromosomal duplication. We find that the chemokines C-X-C motif ligand chemokine-1 (CXCL1) and macrophage chemoattractant protein-1 (MCP1) are commonly upregulated in all three congruent models and in clinical patient samples. The development of congruent models of a single genetic disease using somatic cells from a common patient will facilitate the search for convergent phenotypes.