Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs
Molecular and functional resemblance of differentiated cells derived from isogenic human iPSCs and SCNT-derived ESCs
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DOI：
10.1073/pnas.1708991114
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发表时间：
2017-12-26
影响因子：
11.1
通讯作者：
Wu, Joseph C.
中科院分区：
文献类型：
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作者：
Zhao, Ming-Tao;Chen, Haodong;Wu, Joseph C.
患者特异性多能干细胞(PSCs)可通过转录因子(即诱导多能干细胞，IPSCs)或体细胞核移植(SCNT)产生。然而，由不同的重编程机制产生的分化细胞的异常和临床前应用仍有待评估。在这里，我们研究了来自遗传相关的人类IPSCs的心肌细胞(PSC-CMS)和内皮细胞(PSC-ECs)、SCNT来源的胚胎干细胞(NT-ESCs)以及体外受精胚胎来源的ESCs(IVF-ESCs)的分子和功能特征以及药物反应。我们发现，来自同基因的IPSCs和NT-ESCs的分化细胞具有相似的谱系基因表达、细胞异质性、生理特性和代谢功能。全基因组转录组和DNA甲基组分析表明，IPSC衍生物(IPSC-CMS和IPSC-ECs)与同基因NT-ESC的同源性比来自IVF-ESCs的更相似。尽管IPSCs和NT-ESCs具有相同的核DNA，但携带不同来源的线粒体DNA，但IPSC和NT-ESCs来源的CMS都可以概括阿霉素诱导的心脏毒性，并且在应激条件下产生的活性氧没有显著差异。我们得出结论，人PSCs分化细胞的分子和功能特征主要归因于遗传组成，而不是重编程机制(SCNT与IPSCs)。因此，人IPSCs可以替代NT-ESCs作为产生患者特异性分化细胞的替代品，用于疾病建模和临床前药物试验。
Patient-specific pluripotent stem cells (PSCs) can be generated via nuclear reprogramming by transcription factors (i.e., induced pluripotent stem cells, iPSCs) or by somatic cell nuclear transfer (SCNT). However, abnormalities and preclinical application of differentiated cells generated by different reprogramming mechanisms have yet to be evaluated. Here we investigated the molecular and functional features, and drug response of cardiomyocytes (PSC-CMs) and endothelial cells (PSC-ECs) derived from genetically relevant sets of human iPSCs, SCNT-derived embryonic stem cells (nt-ESCs), as well as in vitro fertilization embryo-derived ESCs (IVF-ESCs). We found that differentiated cells derived from isogenic iPSCs and nt-ESCs showed comparable lineage gene expression, cellular heterogeneity, physiological properties, and metabolic functions. Genome-wide transcriptome and DNA methylome analysis indicated that iPSC derivatives (iPSC-CMs and iPSC-ECs) were more similar to isogenic nt-ESC counterparts than those derived from IVF-ESCs. Although iPSCs and nt-ESCs shared the same nuclear DNA and yet carried different sources of mitochondrial DNA, CMs derived from iPSC and nt-ESCs could both recapitulate doxorubicin-induced cardiotoxicity and exhibited insignificant differences on reactive oxygen species generation in response to stress condition. We conclude that molecular and functional characteristics of differentiated cells from human PSCs are primarily attributed to the genetic compositions rather than the reprogramming mechanisms (SCNT vs. iPSCs). Therefore, human iPSCs can replace nt-ESCs as alternatives for generating patient-specific differentiated cells for disease modeling and preclinical drug testing.