Iron homeostasis is crucial for a variety of biological processes, but the biological role of iron homeostasis in pluripotent stem cells (PSCs) remains largely unknown. The present study aimed to determine whether iron homeostasis is involved in maintaining the pluripotency of human PSCs (hPSCs). We found that the intracellular depletion of iron leads to a rapid downregulation of NANOG and a dramatic decrease in the self-renewal of hPSCs as well as spontaneous and nonspecific differentiation. Moreover, long-term depletion of iron can result in the remarkable cell death of hPSCs via apoptosis and necrosis pathways. Additionally, we found that the depletion of iron increased the activity of lipoprotein-associated phospholipase A2 (LP-PLA2) and the production of lysophosphatidylcholine, thereby suppressing NANOG expression by enhancer of zeste homolog 2-mediated trimethylation of histone H3 lysine 27. Consistently, LP-PLA2 inhibition abrogated iron depletion-induced loss of pluripotency and differentiation. Altogether, the findings of our study demonstrates that iron homeostasis, acting through glycerophospholipid metabolic pathway, is essential for the pluripotency and survival of hPSCs. STEM CELLS 2019;37:489-503
SIGNIFICANCE STATEMENTIron homeostasis is essential for various biological processes. In this study, it was first demonstrated that iron deficiency could severely impair the pluripotency and differentiation of hESCs/ hiPSCs through the downregulation of NANOG by LysoPC-mediated H3K27me3. In addition, long-term iron deficiency reduced the survival and promoted apoptosis in hESCs/hiPSCs. Findings provide novel insights into the underlying mechanisms of iron homeostasis in maintaining the pluripotency and self-renewal of hESCs/hiPSCs