Abstract
Neurons of the central nervous system (CNS) that project long axons into the spinal cord have a poor axon regenerative capacity compared to neurons of the peripheral nervous system. The corticospinal tract (CST) is particularly notorious for its poor regeneration. Because of this, traumatic spinal cord injury (SCI) is a devastating condition that remains as yet uncured. Based on our recent observations that direct neuronal interleukin-4 (IL-4) signaling leads to repair of axonal swellings and beneficial effects in neuroinflammation, we hypothesized that IL-4 acts directly on the CST. Here, we developed a tissue culture model for CST regeneration and found that IL-4 promoted new growth cone formation after axon transection. Most importantly, IL-4 directly increased the regenerative capacity of both murine and human CST axons, which corroborates its regenerative effects in CNS damage. Overall, these findings serve as proof-of-concept that our CST regeneration model is suitable for fast screening of new treatments for SCI.
Highlights
Axon tracts in the spinal cord regenerate poorly, with the corticospinal tract (CST) being the least effective regenerator (Schiwy et al 2009)
Using insulin-like growth factor-1 (IGF-1) as a proof-of-principle and IL-4 as test substance, we validated the CST regeneration assay and found that IL-4 significantly increased the formation of new growth cones after axon transection
Among all tracts in the spinal cord, the CST is the tract with the lowest capacity to regenerate (Schiwy et al 2009)
Summary
Axon tracts in the spinal cord regenerate poorly, with the corticospinal tract (CST) being the least effective regenerator (Schiwy et al 2009). This is thought to be due to Nicholas Hanuscheck, Andrea Schnatz, and Carine Thalman have contributed as first authors. We discovered a neuron-specific fast direct interleukin-4 receptor (IL-4R) signaling pathway leading to neuroprotection (Vogelaar et al 2018; Walsh et al 2015). These observations led to the hypothesis that IL-4 may act directly on the CST. Combined with IL-4 effects on outgrowth in human neuronal cultures, these models provide evidence for the direct regenerative effects of IL-4 and are suitable for the screening of putative growth-promoting treatments for traumatic CNS injury
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