Iron Homeostasis Determines Fate of Human Pluripotent Stem Cells Via Glycerophospholipids-Epigenetic Circuit

Abstract

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

Iron overload inhibits self‐renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species

“…Previous studies have indicated that iron homeostasis is crucial for various kinds of stem cell. For example, iron overload can impact the self‐renewal and function of hematopoietic stem cells and progenitor cells [23,24], whereas iron deficiency impairs the pluripotency of hESCs/hiPSCs [15]. Besides, it has been reported that iron deficiency inhibited the expression of stemness markers and spherogenesis in cancer stem cells [25].…”

“…Human ESCs (H1‐ESCs) and iPSCs (AC‐iPSCs) were cultured as described in our previous study [15]. In brief, cells were cultured in E8 pluripotent stem cell culture medium (STEMCELL Technology, Vancouver, British Columbia, Canada) at a temperature of 37 °C in 5% CO 2 .…”

“…For example, it has been clarified that specific targeting of iron homeostasis in cancer stem cells can increase the cancer therapy [14]. Besides, our group discovered that iron deficiency caused inhibition of pluripotency in hESCs/hiPSCs [15]. However, the effect of iron overload in iPSCs or ESCs has not yet been reported.…”

MgFe‐LDH Nanoparticles: A Promising Leukemia Inhibitory Factor Replacement for Self‐Renewal and Pluripotency Maintenance in Cultured Mouse Embryonic Stem Cells

“…Apart from the lower requirement and tolerance for aluminum ions than iron ions in mice, it has been reported that iron ions can also affect the self‐renewal of ESCs. [ 26–29 ] Hence, we proposed to replace Al ions with Fe ions for LDH modification.…”

YAP/TEAD3 signal mediates cardiac lineage commitment of human‐induced pluripotent stem cells

“…Cells were cultured as described in our previous work (Han et al, 2019). Briefly, cells were maintained in Essential 8 medium (STEMCELL Technologies) and subcultured every 3 to 4 days.…”