Skamagki Maria, Correia Cristina, Yeung Percy, Baslan Timour, Beck Samuel, Zhang Cheng, Ross Christian A, Dang Lam, Liu Zhong, Giunta Simona, Chang Tzu-Pei, Wang Joye, Ananthanarayanan Aparna, Bohndorf Martina, Bosbach Benedikt, Adjaye James, Funabiki Hironori, Kim Jonghwan, Lowe Scott, Collins James J, Lu Chi-Wei, Li Hu, Zhao Rui, Kim Kitai
Cancer Biology and Genetics Program, Center for Cell Engineering, Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute for Cancer Research, and Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55904, USA.
Nat Cell Biol. 2017 Sep;19(9):1037-1048. doi: 10.1038/ncb3598. Epub 2017 Aug 28.
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.
用于生成可移植组织的诱导多能干细胞（iPSC）可能对老年患者特别有益，因为他们更容易患上退行性疾病。然而，与年轻供体来源的iPSC相比，老年供体来源的iPSC（A-iPSC）表现出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-iPSC表现出过量的谷胱甘肽介导的活性氧（ROS）清除活性，这会阻断DNA损伤反应和凋亡，并使具有基因组不稳定性的细胞得以存活。我们发现多能性因子ZSCAN10在A-iPSC中表达不佳，在A-iPSC重编程过程中，将ZSCAN10添加到四个山中因子（OCT4、SOX2、KLF4和c-MYC）中可使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的基因组不稳定性最终将提高我们从老年患者自身细胞中生成组织相容性功能性组织用于安全移植的能力。
