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Published on: September 20, 2024
Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution
Jacob S Heng1,2, Amir Rattner1, Genevieve L Stein-O'Brien2,3
1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Abstract:
The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO (Ndp ) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypovascularization of the retina produces chronic hypoxia of inner nuclear-layer (INL) neurons and Muller glia. We used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13C-glucose to compare WT and Ndp retinas. In Ndp retinas, we observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and we find a metabolic shift that combines reduced flux through the TCA cycle with increased synthesis of serine, glycine, and glutathione. We also used single-cell RNA sequencing to compare the responses of individual cell types in Ndp retinas with those in the hypoxic cerebral cortex of mice that were housed for 1 week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the response of Muller glia in the Ndp retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression program, which likely underlies the adaptive neoangiogenic response to chronic hypoxia. These analyses of retina and brain transcriptomes at single-cell resolution reveal both shared and cell type-specific changes in gene expression in response to chronic hypoxia, implying both shared and distinct cell type-specific physiologic responses.
Insights
Chronic hypoxia in the mammalian central nervous system (CNS) triggers cell-specific gene expression and metabolic shifts. Retinal Muller glia and vascular cells show adaptive responses, sharing similarities with hypoxic brain tissue.
Area of Science:
- Neuroscience
- Cell Biology
- Metabolomics
Background:
- Mammalian central nervous system (CNS) tolerates chronic hypoxia, but cell-specific responses remain unclear.
- Familial exudative vitreoretinopathy (FEVR) models chronic retinal hypoxia due to developmental hypovascularization.
- Inner nuclear layer (INL) neurons and Muller glia are affected by retinal hypoxia in Norrin KO (Ndp) mice.
Purpose of the Study:
- To systematically characterize cell type-specific responses to chronic hypoxia in the mammalian CNS.
- To compare hypoxic responses in the retina and cerebral cortex at single-cell resolution.
- To investigate metabolic shifts and gene expression changes in response to chronic hypoxia.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of retinal and cerebral cortex tissues.
- Untargeted metabolomics and 13C-glucose metabolite labeling.
- Comparative analysis of gene expression in WT and Ndp-/- retinas versus hypoxic cerebral cortex.
Main Results:
- Ndp-/- retinas exhibit hypoxia-consistent gene expression in Muller glia and retinal neurons.
- Metabolic reprogramming in Ndp-/- retinas includes reduced TCA cycle flux and increased serine, glycine, and glutathione synthesis.
- Glial responses in the hypoxic cerebral cortex resemble those of Muller glia in Ndp-/- retinas.
- Vascular endothelial cells in both retina and brain activate a tip cell program, suggesting neoangiogenesis.
Conclusions:
- Chronic hypoxia induces both shared and cell type-specific transcriptomic and metabolic changes in the CNS.
- Muller glia and vascular endothelial cells display conserved adaptive responses to hypoxia across different CNS regions.
- Single-cell resolution reveals distinct cellular mechanisms underlying CNS adaptation to chronic hypoxia.
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