Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo, SP 05508 900, Brazil.
Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, Rua do Matão, 277, São Paulo, SP 05508-090, Brazil.
Mutat Res. 2013 Jan-Mar;752(1):25-35. doi: 10.1016/j.mrrev.2012.09.001. Epub 2012 Sep 23.
All living cells utilize intricate DNA repair mechanisms to address numerous types of DNA lesions and to preserve genomic integrity, and pluripotent stem cells have specific needs due to their remarkable ability of self-renewal and differentiation into different functional cell types. Not surprisingly, human stem cells possess a highly efficient DNA repair network that becomes less efficient upon differentiation. Moreover, these cells also have an anaerobic metabolism, which reduces the mitochondria number and the likelihood of oxidative stress, which is highly related to genomic instability. If DNA lesions are not repaired, human stem cells easily undergo senescence, cell death or differentiation, as part of their DNA damage response, avoiding the propagation of stem cells carrying mutations and genomic alterations. Interestingly, cancer stem cells and typical stem cells share not only the differentiation potential but also their capacity to respond to DNA damage, with important implications for cancer therapy using genotoxic agents. On the other hand, the preservation of the adult stem cell pool, and the ability of cells to deal with DNA damage, is essential for normal development, reducing processes of neurodegeneration and premature aging, as one can observe on clinical phenotypes of many human genetic diseases with defects in DNA repair processes. Finally, several recent findings suggest that DNA repair also plays a fundamental role in maintaining the pluripotency and differentiation potential of embryonic stem cells, as well as that of induced pluripotent stem (iPS) cells. DNA repair processes also seem to be necessary for the reprogramming of human cells when iPS cells are produced. Thus, the understanding of how cultured pluripotent stem cells ensure the genetic stability are highly relevant for their safe therapeutic application, at the same time that cellular therapy is a hope for DNA repair deficient patients.
所有活细胞都利用复杂的 DNA 修复机制来解决多种类型的 DNA 损伤，并维护基因组的完整性。由于其自我更新和分化为不同功能细胞类型的非凡能力，多能干细胞有特定的需求。毫不奇怪，人类干细胞拥有高效的 DNA 修复网络，但在分化过程中效率会降低。此外，这些细胞还具有无氧代谢，这会减少线粒体数量和氧化应激的可能性，而氧化应激与基因组不稳定性高度相关。如果 DNA 损伤得不到修复，人类干细胞很容易衰老、死亡或分化，这是它们的 DNA 损伤反应的一部分，以避免携带突变和基因组改变的干细胞的增殖。有趣的是，癌症干细胞和典型的干细胞不仅具有分化潜能，而且具有应对 DNA 损伤的能力，这对使用遗传毒性药物进行癌症治疗具有重要意义。另一方面，保持成体干细胞库的完整性，以及细胞应对 DNA 损伤的能力，对于正常发育至关重要，可以减少神经退行性疾病和过早衰老的过程，这在许多具有 DNA 修复过程缺陷的人类遗传疾病的临床表型中可以观察到。最后，最近的一些发现表明，DNA 修复在维持胚胎干细胞和诱导多能干细胞 (iPS) 细胞的多能性和分化潜能方面也起着至关重要的作用。在产生 iPS 细胞时，DNA 修复过程似乎对于人类细胞的重编程也是必要的。因此，了解培养的多能干细胞如何确保遗传稳定性对于它们的安全治疗应用非常重要，同时细胞治疗也是 DNA 修复缺陷患者的希望。
