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

Abstract

Failure of central nervous system (CNS) 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 localized cuprizone injection promoted axon regeneration. We also present a website for comparing the gene expression of scRNA-seq-profiled normal and injured optic nerve oligodendrocyte lineage cells.

Local glycolysis supports injury-induced axonal regeneration

“…Indeed, Schwann cells have been shown to support regeneration in the PNS via increased glycolytic activity and lactate shuttle to the axons 43 . On the other hand, in the context of optic nerve crush, resident oligodendrocytes were shown to undergo demyelination and partial cell death 47 . How this disrupted environment affects the metabolic support to injured and regrowing axons is unclear, but at least during the first phases of regeneration it is reasonable to speculate that the axons could rely primarily on intrinsic glucose metabolism rather than metabolic coupling with glia.…”