Recovery of genomic stability by ZSCAN10 in induced pluripotent stem cells from aged donors. Mus musculus

Induced pluripotent stem cells (iPSC), which are generated from a patient’s own cells and used to produce transplantable tissues, may particularly benefit older patients who are more likely to suffer from degenerative diseases. However, iPSC generated from aged donors (A-iPSC) exhibit higher genomic instability, defects in apoptosis, and a blunted DNA damage response compared to iPSC generated from younger donors (Y-iPSC). This raises significant safety concerns, as transplantable tissues produced from A-iPSC may be functionally impaired and carry a higher risk of cancer development. When we consider the complex genomic and epigenetic variations that occur during aging, the genomic instability in A-iPSC is likely caused by multiple mechanims. Here, we introduce the first step toward unraveling this question with the discovery of a mechanism that contributes to A-iPSC instability. We demonstrated that A-iPSC exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and leads to genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSC and addition of ZSCAN10 with the four Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC) used in iPSC reprogramming normalizes ROS/glutathione homeostasis and the DNA damage response and recovers A-iPSC genomic stability. Restoring the genomic stability of A-iPSC will ultimately enhance our ability to produce histocompatible functional tissues from patient’s own cells that are safe for transplantation. Overall design: Total RNA from Y-SC, A-SC, YiPSCS, AiPSCS, AiSPCS+Z and ESC were labeled with Cy3. Samples were hybridized to a MouseRef-8 v2.0 Expression BeadChip (Illumina, San Diego, CA, http://www.illumina.com), according to the manufacturer’s protocol. Arrays were scanned with a BeadChip Reader (Illumina).