Publication

Targeted regeneration of spinal cord neurons across a complete injury restores walking

Marco Milano
2023
Thèse EPFL
Résumé

Spinal cord injury (SCI) interrupts axonal connections between the brain and the spinal cord, and is characterized by a spectrum of sensorimotor and autonomic impairments. While spontaneous recovery is limited, recent studies have shown that functional improvements can be greatly augmented via rehabilitative approaches based on targeted epidural electrical stimulation that recapitulates the natural pattern of spinal activation. Nevertheless, these strategies depend on the presence of spared axonal connections, and are consequently constrained in the extent of elicitable recovery, and inapplicable in the case of very severe or anatomically complete SCI. It is therefore agreed that future therapies for SCI will require strategies to repair the injured spinal cord by stimulating severed axons to regenerate across the tissue lesions.Despite this need, axons from adult mammalian central nervous system (CNS) neurons are characterized by intrinsic incapacity of spontaneous regeneration. Research in the last several decades has uncovered multiple mechanisms underlying CNS regenerative failure, and a recent approach developed by our group has identified the requirements to induce experimental axon regrowth across anatomically complete SCI in rodents. Yet, while robust regeneration could be elicited with this and other strategies, restoring meaningful function after such injuries has been elusive.In the work presented in this thesis, we sought to build on our previous approach by identifying, and then providing, requirements that are missing for recovery. Concretely, we sought to determine whether restoring neurological function requires regeneration of specific subpopulations of neurons directed to their natural target region.To address these questions, we shifted our attention to a specific model of severe but incomplete SCI, following which natural reorganization of spinal circuits is associated with spontaneous recovery of walking. We performed projection-specific and comparative single-nucleus RNA sequencing to uncover the transcriptional phenotype and connectome of neuronal subpopulations involved in natural spinal cord repair, and identified a molecularly defined population of excitatory projection neurons in the thoracic spinal cord that extend axons to the lumbar spinal cord where walking execution centers reside.We optimized our previous strategy to provide sustained chemoattraction to the identified neuronal subpopulation. We showed that regrowing axons from these neurons across anatomically complete SCI and guiding them to their appropriate target region in the lumbar spinal cord restores walking in mice, whereas regeneration of axons simply across the lesion has no effect. Selective loss-of-function experiments further revealed that recovery is largely dependent on regeneration of the characterized neuronal subtype.These results demonstrate that mechanism-based repair strategies that recapitulate the natural topology of molecularly defined neuronal subpopulations can restore neurological functions following anatomically complete SCI.

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Concepts associés (37)
Traumatisme médullaire
Un traumatisme médullaire ou traumatisme de la moelle épinière (ou moelle spinale) met en jeu le pronostic vital immédiat ou retardé. Il est à l'origine de troubles moteurs et sensitifs, et de troubles des fonctions neuro-végétatives. La médicalisation systématique et les progrès de la prise en charge pré-hospitalière ont permis d'améliorer considérablement la survie de ces blessés. L'évolution des connaissances, notamment dans la physiopathologie des lésions cellulaires, fait proposer régulièrement de nouvelles attitudes thérapeutiques, parfois controversées.
Spinal cord injury research
Spinal cord injury research seeks new ways to cure or treat spinal cord injury in order to lessen the debilitating effects of the injury in the short or long term. There is no cure for SCI, and current treatments are mostly focused on spinal cord injury rehabilitation and management of the secondary effects of the condition. Two major areas of research include neuroprotection, ways to prevent damage to cells caused by biological processes that take place in the body after the injury, and neuroregeneration, regrowing or replacing damaged neural circuits.
Moelle spinale
La moelle spinale (selon la nouvelle nomenclature), ou moelle épinière (dans l’ancienne nomenclature), désigne la partie du système nerveux central qui prolonge la moelle allongée appartenant au tronc cérébral. Elle est contenue dans le canal rachidien (canal formé par la superposition des foramens vertébraux), qui la soutient et la protège. Elle est constituée de neurones et de cellules gliales. Sa fonction principale est la transmission des messages nerveux entre le cerveau et le reste du corps.
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Learn how to digitally reconstruct a single neuron to better study the biological mechanisms of brain function, behaviour and disease.
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Learn how to digitally reconstruct a single neuron to better study the biological mechanisms of brain function, behaviour and disease.
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