Chen I-Chung, Hernandez Christine, Xu Xueping, Cooney Austin, Wang Yufeng, McCarrey John R
1 Department of Biology, University of Texas at San Antonio , San Antonio, Texas.
2 Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center , Houston, Texas.
Stem Cells Dev. 2016 Nov 15;25(22):1698-1708. doi: 10.1089/scd.2016.0221. Epub 2016 Oct 12.
Pluripotent stem cells hold the potential to form the basis of novel approaches to treatment of disease in vivo as well as to facilitate the generation of models for human disease, providing powerful avenues to discovery of novel diagnostic biomarkers and/or innovative drug regimens in vitro. However, this will require extensive maintenance, expansion, and manipulation of these cells in culture, which raises a concern regarding the extent to which genetic integrity will be preserved throughout these manipulations. We used a mutation reporter (lacI) transgene approach to conduct direct comparisons of mutation frequencies in cell populations that shared a common origin and genetic identity, but were induced to undergo transitions in cell fate between pluripotent and differentiated states, or vice versa. We confirm that pluripotent cells normally maintain enhanced genetic integrity relative to that in differentiated cells, and we extend this finding to show that dynamic transformations in the relative stringency at which genetic integrity is maintained are associated with transitions between pluripotent and differentiated cellular states. These results provide insight into basic biological distinctions between pluripotent and differentiated cell types that impact genetic integrity in a manner that is directly relevant to the potential clinical use of these cell types.
多能干细胞有潜力成为体内疾病治疗新方法的基础，也有助于生成人类疾病模型，为体外发现新型诊断生物标志物和/或创新药物方案提供有力途径。然而，这需要在培养中对这些细胞进行大量的维持、扩增和操作，这引发了人们对在这些操作过程中基因完整性能在多大程度上得以保留的担忧。我们采用了一种突变报告基因（lacI）转基因方法，对具有共同起源和遗传特性，但被诱导在多能状态和分化状态之间进行细胞命运转变，或反之亦然的细胞群体中的突变频率进行直接比较。我们证实，相对于分化细胞，多能细胞通常能维持更高的基因完整性，并且我们进一步扩展这一发现，表明在维持基因完整性的相对严格程度上的动态转变与多能细胞和分化细胞状态之间的转变相关。这些结果为多能细胞和分化细胞类型之间的基本生物学差异提供了见解，这些差异以与这些细胞类型的潜在临床应用直接相关的方式影响基因完整性。
