Abstract
Embryonic stem cells (ESCs) are pluripotent cells with indefinite self-renewal ability and differentiation properties. To function properly and maintain genomic stability, ESCs need to be endowed with an efficient repair system as well as effective redox homeostasis. In this study, we investigated different aspects involved in ESCs’ response to iron accumulation following stable knockdown of the ferritin heavy chain (FTH1) gene, which encodes for a major iron storage protein with ferroxidase activity. Experimental findings highlight unexpected and, to a certain extent, paradoxical results. If on one hand FTH1 silencing does not correlate with increased ROS production nor with changes in the redox status, strengthening the concept that hESCs are extremely resistant and, to a certain extent, even refractory to intracellular iron imbalance, on the other, the differentiation potential of hESCs seems to be affected and apoptosis is observed. Interestingly, we found that FTH1 silencing is accompanied by a significant activation of the nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signaling pathway and pentose phosphate pathway (PPP), which crosstalk in driving hESCs antioxidant cascade events. These findings shed new light on how hESCs perform under oxidative stress, dissecting the molecular mechanisms through which Nrf2, in combination with PPP, counteracts oxidative injury triggered by FTH1 knockdown.
Highlights
Introduction published maps and institutional affilAn impaired intracellular balance between reactive oxygen species (ROS) production and clearance is responsible for establishing an oxidative stress status, eventually leading to lethal consequences [1] for the cells
Colonies originated from FTH1-KD hESCs were more flattened than those of shSCR control (Supplementary Figure S1A), and alkaline significant reduction in NANOG expression [22]
FTH1-silenced hESCs (Figure 4G, Supplementary Figure S5D,H). These results provide strong evidence that FTH1 silencing induces apoptosis in hESCs and triggers the activation of DNA-damage response programs, which are efficiently counteracted by the survival mechanisms described above
Summary
Introduction published maps and institutional affilAn impaired intracellular balance between reactive oxygen species (ROS) production and clearance is responsible for establishing an oxidative stress status, eventually leading to lethal consequences [1] for the cells. ROS are able to elicit a wide spectrum of responses; slight variations in their concentration may produce profound and opposite effects in distinct cell types [2]. High levels of ROS, predominantly produced by mitochondrial respiration, are classically linked to cellular damage, DNA damage, and apoptosis. A large body of data recognizes ROS as signaling messengers involved in many biological processes, including DNA synthesis, modulation of gene expression, cellular respiration, protein–protein interactions [3], as well as activation of critical pathways such as protein kinase B (AKT) and NF-κB signaling [4]. In hESCs, constant exposure to high levels of ROS was shown to induce cell cycle arrest and apoptosis [5]; by regulating the redox state, ROS target important aspects of pluripotency, such as metabolism, iations
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