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other·ophthalmology, neuro-ophthalmology, preclinical research, neurology, biomedical research·PMC10163352

Post-injury born oligodendrocytes incorporate into the glial scar and contribute to the inhibition of axon regeneration

Development (Cambridge, England) · 7 authors, 1 centre

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TL;DR

In a mouse model of optic nerve crush, newly born oligodendrocytes incorporated into the glial scar and inhibited axon regeneration; this inhibition was reduced by a demyelinating diet (cuprizone) which also enhanced axon regeneration stimulated by Pten knockdown.

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This preclinical mouse study investigated why regenerating axons in the central nervous system stall before reaching their targets. Using single-cell RNA sequencing and immunohistology after optic nerve crush, the authors found that post-injury born oligodendrocyte lineage cells repopulated the injury site and incorporated into the glial scar. Administering a cuprizone-containing diet induced demyelination, which reduced the presence of these new oligodendrocytes in the scar. Combining this demyelination with Pten knockdown (a known pro-regenerative stimulus) significantly enhanced axon regeneration compared to Pten knockdown alone. Localized intravitreal injection of cuprizone also promoted regeneration. The study suggests that the interaction of regenerating axons with live, newly formed oligodendrocytes is a barrier to growth.

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other

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ophthalmology

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100% · A

ORIGINAL PAPER

PMC10163352

Post-injury born oligodendrocytes incorporate into the glial scar and contribute to the inhibition of axon regeneration

Development (Cambridge, England)

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ABSTRACT

ABSTRACT Failure of central nervous system projection neurons to spontaneously regenerate long-distance axons underlies irreversibility of white matter pathologies. A barrier to axonal regenerative research is that the axons regenerating in response to experimental treatments stall growth before reaching post-synaptic targets. Here, we test the hypothesis that the interaction of regenerating axons with live oligodendrocytes, which were absent during developmental axon growth, contributes to stalling axonal growth. To test this hypothesis, first, we used single cell RNA-seq (scRNA-seq) and immunohistology to investigate whether post-injury born oligodendrocytes incorporate into the glial scar after optic nerve injury. Then, we administered demyelination-inducing cuprizone and stimulated axon regeneration by Pten knockdown (KD) after optic nerve crush. We found that post-injury born oligodendrocyte lineage cells incorporate into the glial scar, where they are susceptible to the demyelination diet, which reduced their presence in the glial scar. We further found that the demyelination diet enhanced Pten KD-stimulated axon regeneration and that localized cuprizone injection promoted axon regeneration. We also present a resource for comparing the gene expression of scRNA-seq-profiled normal and injured optic nerve oligodendrocyte lineage cells.

CITATION EXPORT

Jian Xing, Agnieszka Lukomska, Bruce A. Rheaume et al.. Post-injury born oligodendrocytes incorporate into the glial scar and contribute to the inhibition of axon regeneration. Development (Cambridge, England). (2023). https://doi.org/10.1242/dev.201311

AUTHORS

7 · 1 CENTRES

Jian Xing, Agnieszka Lukomska, Bruce A. Rheaume, Juhwan Kim, Muhammad S. Sajid, Ashiti Damania, Ephraim F. Trakhtenberg

Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA