Post-injury born oligodendrocytes integrate into the glial scar and inhibit growth of regenerating axons by premature myelination

Abstract

Pathologies of the central nervous system (CNS) white matter often result in permanent functional deficits because mature mammalian projection neurons fail to regenerate long-distance axons after injury. A major barrier to axonal regenerative research is that the CNS axons that regenerate in response to experimental treatments stall growth before reaching their post-synaptic targets. Here, we test the hypothesis that premature, de novo, myelination of regenerating axons stalls their growth, even after bypassing the glial scar. To test this hypothesis, first, we used single cell RNA-seq (scRNA-seq) and immunohistological analysis to investigate whether post-injury born oligodendrocytes integrate into the glial scar after optic nerve injury. Then, we used a multiple sclerosis model of demyelination concurrently with the stimulation of axon regeneration by Pten knockdown (KD) in projection neurons after optic nerve injury. We found that post-injury born oligodendrocytes integrate into the glial scar, where they are susceptible to the demyelination treatment, which prevented premature myelination, and thereby enhanced Pten KD-stimulated axon regeneration. We also present a website for comparing the gene expression of scRNA-seq-profiled optic nerve oligodendrocytes under physiological and pathophysiological conditions.