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

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.

SUBMITTER: Xing J

PROVIDER: S-EPMC10163352 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Xing Jian J Lukomska Agnieszka A Rheaume Bruce A BA Kim Juhwan J Sajid Muhammad S MS Damania Ashiti A Trakhtenberg Ephraim F EF

Development (Cambridge, England) 20230427 8

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 axon ...[more]

PMID: 36971369

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Project description:Regeneration after spinal cord injury (SCI) is limited by the presence of a glial scar and inhibitory cell signaling pathways that favor scar formation over regrowth of endogenous neurons. Tissue engineering techniques, including the use of allografted neural networks, have shown promise for nervous system repair in prior studies. Through the use of a minimally invasive injury model in rats, we describe the implantation of micro-tissue engineered neural networks (micro-TENNs) across a region of SCI, spanning the glial scar to promote axonal regeneration. Forty-three female Sprague-Dawley rats were included in this study. Micro-TENNs were preformed in vitro before implant, and comprised rat sensory dorsal root ganglion (DRG) neurons projecting long bundled axonal tracts within the lumen of a biocompatible hydrogel columnar encasement (1.2 cm long; 701 μm outer diameter × 300 μm inner diameter). Animals were injured using a 2F embolectomy catheter inflated within the epidural space. After a 2-week recovery period, micro-TENNs were stereotactically implanted across the injury. Animals were euthanized at 1 week and 1 month after implantation, and the tissue was interrogated for the survival of graft DRG neurons and outgrowth of axons. No intraoperative deaths were noted with implantation of the micro-TENNs to span the injury cavity. Graft DRG axons were found to survive at 1 week postimplant within the hydrogel encasement. Graft-derived axonal outgrowth was observed within the spinal cord up to 4.5 mm from the implant site at 1 month postinjury. Limited astroglial response was noted within the host, suggesting minimal trauma and scar formation in response to the graft. Micro-TENN sensory neurons survive and extend axons into the host spinal cord following a minimally invasive SCI in rats. This work serves as the foundation for future studies investigating the use of micro-TENNs as a living bridge to promote recovery following SCI. Impact statement As spinal cord injury pathology develops, the establishment of a glial scar puts an end to the hope of regeneration and recovery from the consequent neurological deficits. Therefore, growing attention is given to bioengineered scaffolds that can bridge the lesions bordered by this scar tissue. The utilization of longitudinally aligned preformed neural networks-referred to as micro-tissue engineered neural networks (TENNs)-presents a promising opportunity to provide a multipurpose bridging strategy that may take advantage of several potential mechanisms of host regeneration. In addition to providing physical support for regenerating spinal cord axons, micro-TENNs may serve as a functional "cable" that restores lost connections within the spinal cord.

Dataset Information

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

Publications

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

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