Glycogen synthase kinase-3 inhibition sensitizes human induced pluripotent stem cells to thiol-containing antioxidants induced apoptosis.

摘要: Inhibition of glycogen synthase kinase 3 (GSK3) is an extensively used strategy to activate Wnt pathway for pluripotent stem cell (PSC) differentiation. However, the effects such inhibition on PSCs, besides upregulating pathway, have rarely been investigated despite that GSK3 broadly involved in other cellular activities as insulin signaling and growth/survival regulation. Here we describe a previously unknown synergistic effect between (e.g., Chir99021 LY2090314) various normally non-toxic thiol-containing antioxidants N-acetylcysteine, NAC) induction apoptosis human induced cells (iPSCs). Neither nor individually significant apoptosis, whereas their combined treatment resulted rapid extensive with substantial caspase activity observed within 3h over 90% decrease viability after 24h. We confirmed generality this phenomenon multiple independent iPSCs lines, thiol-based distinct inhibitors. Mechanistically, demonstrated rapamycin could substantially reduce death, suggesting critical role mammalian target (mTOR). Akt dysregulation was also found partially contribute but not primary cause. Further, coordinated proapoptotic detected mouse ESCs present another line: breast cancer line (MDA-MB-231). Given wide use biomedical research: from iPSC differentiation intervention neuronal diseases, researchers can potentially take advantage or avoid improved experimental clinical outcome.