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Oxygen impairs oligodendroglial development via oxidative stress and reduced expression of HIF-1α
Christina Brill1, Till Scheuer1,2, Christoph Bührer1
1Department of Neonatology, Charité University Medical Center, Berlin, Germany.
Insights
High oxygen levels damage oligodendroglial precursor cells (OPCs) in preterm infants by impairing development and increasing oxidative stress. Reduced Hypoxia-Inducible-Factor-1-alpha (Hif-1α) activity contributes to these negative effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Premature infants face risks from elevated oxygen levels, potentially harming oligodendroglial precursor cells (OPCs).
- Fetal OPCs normally develop in low oxygen environments, unlike those cultured at room air oxygen levels.
- Understanding oxygen's impact on OPCs is crucial for preventing neurodevelopmental issues in preterm infants.
Purpose of the Study:
- To investigate the effects of increased oxygen tension on OPC development, maturation, and associated molecular changes.
- To explore the role of Hypoxia-Inducible-Factor-1-alpha (Hif-1α) in mediating hyperoxia-induced OPC damage.
- To assess oxidative stress, apoptosis, and proliferation markers in OPCs under varying oxygen conditions.
Main Methods:
- Rat OPCs and OLN93 cells were cultured at 5% and 21% oxygen.
- Assessed cell maturation markers (e.g., MBP, CNP), oxidative stress (nitrotyrosine, NRF2, SOD2), apoptosis (TUNEL), and proliferation (Ki67).
- Investigated Hif-1α activity using luciferase reporter assays and Hif-1α-knockdown experiments.
Main Results:
- Culture at 21% oxygen decreased OPC proliferation and arborization, and reduced expression of maturation markers (MBP, CNP, Olig1, Sox9, Sox10).
- Elevated oxygen increased oxidative stress markers (nitrotyrosine, NRF2, SOD2) without affecting apoptosis.
- Hif-1α activity was higher at 5% oxygen; Hif-1α knockdown at 5% oxygen mimicked 21% oxygen effects on MBP and CNP expression.
Conclusions:
- Culturing OPCs at 21% oxygen negatively impacts their development and maturation.
- Hyperoxia-induced changes involve increased oxidative stress and reduced expression of Hif-1α-regulated genes.
- Maintaining appropriate oxygen levels is vital for OPC development and potentially for preventing brain injury in preterm infants.
Abstract:
The premature increase of oxygen tension may contribute to oligodendroglial precursor cell (OPC) damage in preterm infants. Fetal OPCs are exposed to low oxygen tissue tensions not matched when cells are cultured in room air. Maturation (A2B5, O4, O1, MBP, CNP, arborization), oxidative stress (nitrotyrosine Western blot, NRF2 and SOD2 expression), apoptosis (TUNEL), proliferation (Ki67), and expression of transcription factors regulated by Hypoxia-Inducible-Factor-1-alpha (Hif-1α) expressed in OPCs (Olig1, Olig2, Sox9, Sox10) were assessed in rat OPCs and OLN93 cells cultured at 5% O2 and 21% O2. Influences of Hif-1α were investigated by Hif-1α luciferase reporter assays and Hif-1α-knockdown experiments. At 21% O2, cell proliferation was decreased and process arborization of OPCs was reduced. Expression of MBP, CNP, Olig1, Sox9 and Sox10 was lower at 21% O2, while Nrf2, SOD2, nitrotyrosine were increased. Apoptosis was unchanged. Luciferease reporter assay in OLN93 cells indicated increased Hif-1α activity at 5% O2. In OLN93 cells at 5% O2, Hif-1α knockdown decreased the expression of MBP and CNP, similar to that observed at 21% O2. These data indicate that culturing OPCs at 21% O2 negatively affects development and maturation. Both enhanced oxidative stress and reduced expression of Hif-1α-regulated genes contribute to these hyperoxia-induced changes.
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