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Differentiation of Mouse Embryonic Stem Cells into Cortical Interneuron Precursors
Published on: December 3, 2017
The protective role of GPX4 in naïve ESCs is highlighted by induced ferroptosis resistance through GPX4 expression
Seokwoo Park1, Mihn Jeong Park2, Eun-Ji Kwon2
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Abstract:
Ferroptosis, a form of oxidative cell death mediated by lipid peroxidation, is strictly regulated by glutathione peroxidase 4 (GPX4). Knockout of Gpx4 results in embryonic lethality, highlighting its essential role in development. In vitro, mouse embryonic stem cells (mESCs), which represent the naïve pluripotent state, require β-mercaptoethanol (bME) to prevent cell death, unlike human embryonic stem cells, which represent the primed state. We hypothesized that naïve pluripotency is linked to a heightened susceptibility to ferroptosis due to unique metabolic demands and redox imbalances. In this study, we found that bME deprivation induces ferroptosis in naïve ESCs, as evidenced by lipid peroxidation; ferroptosis, however, is less evident in primed ESCs. Mechanistic analyses revealed that active oxidative phosphorylation (OXPHOS) in naïve ESCs increased mitochondrial reactive oxygen species. Consistent with the upregulation of Gpx4 transcripts and OXPHOS-associated gene sets seen in the inner cell mass of blastocysts, stable GPX4 expression conferred resistance to ferroptosis induced by bME withdrawal. These results suggest that the unique redox and metabolic landscape of naïve ESCs highlits a potential requirement for GPX4 in maintaining naïve pluripotency, providing insights into early developmental processes and vulnerabilities.
Insights
Naïve pluripotent stem cells are susceptible to ferroptosis due to metabolic demands. Glutathione peroxidase 4 (GPX4) protects these cells, suggesting its essential role in maintaining pluripotency and early development.
Area of Science:
- Cellular biology
- Developmental biology
- Biochemistry
Background:
- Ferroptosis is a regulated form of cell death driven by lipid peroxidation.
- Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis and essential for embryonic development.
- Mouse embryonic stem cells (mESCs) represent naïve pluripotency and require specific conditions (e.g., β-mercaptoethanol) to survive in vitro.
Purpose of the Study:
- To investigate the link between naïve pluripotency and ferroptosis susceptibility.
- To determine the role of GPX4 in naïve pluripotent stem cells.
- To elucidate the metabolic and redox factors contributing to ferroptosis in different pluripotent states.
Main Methods:
- Comparison of ferroptosis induction in naïve (mESCs) and primed (hESCs) embryonic stem cells upon β-mercaptoethanol deprivation.
- Assessment of lipid peroxidation as an indicator of ferroptosis.
- Mechanistic analysis of oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (ROS) production.
- Evaluation of GPX4 expression and its effect on ferroptosis resistance.
Main Results:
- β-mercaptoethanol deprivation induced significant ferroptosis in naïve ESCs, evidenced by lipid peroxidation.
- Primed ESCs exhibited less ferroptosis compared to naïve ESCs under the same conditions.
- Active OXPHOS in naïve ESCs was associated with increased mitochondrial ROS, contributing to ferroptosis.
- Stable GPX4 expression conferred resistance to ferroptosis induced by β-mercaptoethanol withdrawal.
Conclusions:
- Naïve pluripotency is associated with heightened ferroptosis susceptibility due to unique metabolic and redox environments.
- GPX4 plays a crucial role in protecting naïve pluripotent stem cells from ferroptosis.
- These findings highlight GPX4's potential requirement for maintaining naïve pluripotency and offer insights into early development.
