Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS–glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients’ own cells that are safe for transplantation.

中文翻译：

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ZSCAN10表达可纠正来自老年供体的iPSC的基因组不稳定性

用于产生可移植组织的诱导多能干细胞（iPSC）可能特别有益于老年患者，他们更可能患有退行性疾病。但是，与年轻的供体相比，老年供体（A-iPSC）产生的iPSC具有更高的基因组不稳定性，凋亡缺陷和钝化的DNA损伤反应。我们证明，A-iPSCs表现出过量的谷胱甘肽介导的活性氧（ROS）清除活性，这阻止了DNA损伤反应和细胞凋亡，并允许具有基因组不稳定性的细胞存活。我们发现，多能性因子ZSCAN10在A-iPSC中表达不佳，并且将ZSCAN10添加到四个Yamanaka因子（OCT4，SOX2，A-iPSC重编程过程中的KLF4和c-MYC）使ROS-谷胱甘肽稳态和DNA损伤反应正常化，并恢复了基因组稳定性。纠正A-iPSC的基因组不稳定性，将最终增强我们从可移植安全的老年患者自身细胞产生组织相容性功能组织的能力。