| abstract |
Disclosed are findings that: (a) induced pluripotent stem cells derived from aged donors (A-iPSC) show increased genomic instability, a defect in apoptosis, a defect in glucose metabolism, and a blunted DNA damage response are compared to those derived from young donors (Y-iPSC); and (b) inhibition of excessive glutathione - mediated H202 scavenging activity, found to be associated with A-iPSC and in turn inhibiting DNA damage response and apoptosis, substantially rescues these defects and reduces the oncogenic potential of A-iPSC. Supplementation of pluripotency factor ZSCAN 10 (shown to be poorly activated in A-iPSC and to act upstream of glutathione involvement), e.g., by expression as an adjunct to the four Yamanaka iPSC reprogramming factors, led to substantial recovery of genomic stability, DNA damage response, and apoptosis in A-iPSC through enhancing GLUT3 and normalizing homeostasis of glutathione/H202; GLUT3 (a pluripotent stem cell- specific glucose transporter acting upstream of glutathione and also poorly activated in A-iPSC) has similar effects, indicating that inhibition of glutathione/H202 notably through delivery of ZSCAN 10 and /or GLUT3 and/or an exosome subunit will be clinically useful, resulting in A-iPSC of improved properties and reduced oncogenic potential. |