Glial cholesterol redistribution in hypoxic injury in vitro influences oligodendrocyte maturation and myelination.

Vadanya Shrivastava, Sagar Tyagi, Devanjan Dey, Archna Singh, Jayanth Kumar Palanichamy, Subrata Sinha, J B Sharma, Pankaj Seth, Sudip Sen

Biochimica et biophysica acta. Molecular basis of disease 2024 Dec

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Hypoxic insult to the fetal brain causes loss of vulnerable premyelinating oligodendrocytes and arrested oligodendrocyte differentiation. Astrocytes influence oligodendrocyte differentiation and the astrocytic response to hypoxia could affect oligodendrocyte maturation under hypoxia. To identify pathways by which astrocytes influence oligodendroglial maturation in hypoxic injury, human fetal neural stem cell-derived astrocytes were exposed to 0.2 % oxygen for 48 hours. Transcriptomic analysis revealed the upregulation of the cholesterol-biosynthesis pathway in hypoxia-exposed astrocytes. Hypoxia-exposed primary astrocytes and astrocytic cell line (SVG) showed increased expression of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), squalene epoxidase (SQLE), apolipoprotein E (apoE) and ATP-binding cassette transporter 1 (ABCA1) on qPCR and Western blot. Hypoxic SVG also showed increased cholesterol content in cells and culture supernatants and increased cell surface expression of ABCA1. Interestingly hypoxia-exposed premyelinating oligodendrocytes (Mo3.13) showed reduced cholesterol along with decreased expression of HMGCR and SQLE on qPCR and Western blot. Exogenous cholesterol increased the differentiation of Mo3.13 as measured by increased expression of myelin basic protein (MBP) on flow cytometry. Hypoxia exposure resulted in increased cholesterol transport from astrocytes to oligodendrocytes in cocultures with BODIPY-cholesterol labelled SVG and membrane-labelled Mo3.13. As exogenous cholesterol enhanced oligodendrocyte differentiation, our findings indicate that increased cholesterol synthesis by astrocytes and transport to oligodendrocytes could supplement oligodendroglial maturation in conditions of hypoxic brain injury in neonates. Copyright © 2024 Elsevier B.V. All rights reserved.

Citation

Vadanya Shrivastava, Sagar Tyagi, Devanjan Dey, Archna Singh, Jayanth Kumar Palanichamy, Subrata Sinha, J B Sharma, Pankaj Seth, Sudip Sen. Glial cholesterol redistribution in hypoxic injury in vitro influences oligodendrocyte maturation and myelination. Biochimica et biophysica acta. Molecular basis of disease. 2024 Dec;1870(8):167476