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 表达可纠正老年供体 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）可能特别有利于老年患者，因为他们更有可能患有退行性疾病。然而，与年轻供体产生的 iPSC 相比，老年供体产生的 iPSC (A-iPSC) 表现出更高的基因组不稳定性、细胞凋亡缺陷和 DNA 损伤反应减弱。我们证明 A-iPSC 表现出过度的谷胱甘肽介导的活性氧 (ROS) 清除活性，从而阻止 DNA 损伤反应和细胞凋亡，并允许基因组不稳定的细胞存活。我们发现多能因子 ZSCAN10 在 A-iPSC 中表达较差，并且在 A-iPSC 重编程过程中将 ZSCAN10 添加到四个 Yamanaka 因子（OCT4、SOX2、KLF4 和 c-MYC）中可以使 ROS-谷胱甘肽稳态和 DNA 损伤反应正常化，并恢复基因组稳定性。纠正 A-iPSC 的基因组不稳定性将最终增强我们利用老年患者自身细胞生产可安全移植的组织相容性功能组织的能力。