Abstract
Spinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. Here we report significant locomotor recovery of both hindlimbs after a complete spinal cord crush. This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration. We find collaterals of these AAV-transduced motoneurons projecting to serotonergic neurons in both sides of the raphe nuclei. Hence, the transduction of cortical neurons facilitates the axonal transport and release of hIL-6 at innervated neurons in the brain stem. Therefore, this transneuronal delivery of hIL-6 promotes the regeneration of corticospinal and raphespinal fibers after injury, with the latter being essential for hIL-6-induced functional recovery. Thus, transneuronal delivery enables regenerative stimulation of neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.
Highlights
Spinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons
Besides an inhibitory environment for axonal growth cones caused by myelin or the forming glial scar, the lack of central nervous system (CNS) regeneration is mainly attributed to a developmental decline in the neuron-intrinsic growth capacity of axons per se[1,2,3]
PTEN−/−-induced phosphorylation of S6 was restricted to GFP-positive neurons only (Fig. 1k, l)
Summary
Spinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. We report significant locomotor recovery of both hindlimbs after a complete spinal cord crush This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration. The conditional genetic knockout of the phosphatase and tensin homolog (PTEN−/−) in cortical motor neurons, which leads to an activation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT)/ mTOR signaling pathway, enables some regeneration of CST axons beyond the site of injury[10] This approach facilitated the most robust anatomical regeneration of the CST after a spinal cord crush (SCC) so far[10], it fails to improve functional motor recovery[11].
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