Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability
Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability
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DOI：
10.15252/embj.201694892
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发表时间：
2016-09-15
期刊：
影响因子：
11.4
通讯作者：
Nelson, Timothy J.
中科院分区：
文献类型：
--
作者：
Perales-Clemente, Ester;Cook, Alexandra N.;Nelson, Timothy J.
人类诱导多能干细胞(HiPSCs)克隆之间的功能差异仍然是组装高质量生物库的一个限制。除了人与人之间的可变性之外，人内可变性的根本原因仍然未知。在核重编程中，线粒体引导从氧化代谢到糖酵解代谢的必要转变。此外，线粒体有自己的基因组(线粒体DNA[mtDNA])。在这里，我们对来自19个个体的84个HiPSC克隆进行了线粒体DNA下一代测序(NGS)，其中包括线粒体患者和非线粒体患者。对mtDNA变体的分析表明，通过核重新编程，原始成纤维细胞中存在低水平的潜在致病突变，从而产生突变的hiPSCs，对其分化的后代产生有害影响。具体地说，hIPSC来源的心肌细胞具有扩展的mtDNA突变，与任何描述的人类疾病无关，显示线粒体呼吸受损，这是人内hIPSC变异性的潜在原因。我们建议将mtDNA NGS作为新的筛选标准，以确保药物发现和再生医学中HiPSC的质量。
Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high-quality biorepositories. Beyond inter-person variability, the root cause of intra-person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA [mtDNA]). Herein, we performed mtDNA next-generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non-mitochondrial patients. The analysis of mtDNA variants showed that low levels of potentially pathogenic mutations in the original fibroblasts are revealed through nuclear reprogramming, generating mutant hiPSCs with a detrimental effect in their differentiated progeny. Specifically, hiPSC-derived cardiomyocytes with expanded mtDNA mutations non-related with any described human disease, showed impaired mitochondrial respiration, being a potential cause of intra-person hiPSC variability. We propose mtDNA NGS as a new selection criterion to ensure hiPSC quality for drug discovery and regenerative medicine.