| Autor: |
Katerina Stepankova, Barbora Smejkalova, Lucia Machova-Urdzikova, Katerina Haveliková, Joost Verhaagen, Fred de Winter, Vit Herynek, Jessica Kwok, James Fawcett, Pavla Jendelova |
| Rok vydání: |
2023 |
| Popis: |
Sensory axons cut within the spinal cord do not regenerate spontaneously. This failure is due in part to absence of an appropriate adhesion molecule on sensory axons, able to interact with the CNS environment. Previous work has shown that transduction of sensory neurons with α9 integrin, which combines with endogenous β1 as α9β1 together with the integrin activator kindlin-1 enables regeneration of sensory axons from a dorsal root crush to the brainstem. The integrin provides an adhesion molecule that recognizes Tenascin-C (which is upregulated in damaged spinal cord) and signals to upregulate the regeneration-associated gene programme. Regeneration from sensory neurons transduced with α9 integrin and kindlin-1 was examined after C4 and after T10 dorsal column lesions with C6,7 and L4,5 sensory ganglia injected with AAV1 vectors. In α9 integrin and kindlin-1 treated animals sensory axons regenerated through tenascin-C-expressing connective tissue strands and bridges across the lesion then re-entered CNS tissue. Many axons regenerated rostrally to the level of the medulla but were excluded from the sensory nuclei. Regenerated axons were seen particularly at the white matter/grey matter boundary in the dorsal cord. Many branches into the dorsal horn were seen tipped with synaptic swellings. Stimulation of the sciatic nerve led to many neurons rostral to the injury being activated to express cFos. Behavioural recovery was seen in heat and pressure sensation and tape removal. Treatment of sensory neurons with α9 integrin and kindlin-1 therefore enables partial reconstruction of the spinal sensory pathway.Significance StatementFull recovery from spinal cord injury can only occur if the axon pathways that connect the brain and spinal cord regenerate to restore motor and sensory connections. Neither sensory nor motor axons in mammals can regenerate spontaneously. A critical factor missing in adult neurons is an adhesion molecule that can enable them to interact with the environment of the damaged spinal cord. In this study in rats an integrin adhesion molecule together with its activator was expressed in sensory neurons using a viral vector. Possession of this adhesion molecule enabled sensory axons to regenerate through the spinal cord injury and all the way back to the brainstem, restoring the sensory pathway. The animal regained touch sensation, enabling sensory behaviours. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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