Growth-Promoting Treatment Screening for Corticospinal Neurons in Mouse and Man
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ORIGINAL RESEARCH
Growth‑Promoting Treatment Screening for Corticospinal Neurons in Mouse and Man Nicholas Hanuscheck1 · Andrea Schnatz2 · Carine Thalman1 · Steffen Lerch1 · Yvonne Gärtner1 · Micaela Domingues1 · Lynn Bitar1 · Robert Nitsch3 · Frauke Zipp1 · Christina F. Vogelaar1 Received: 16 October 2019 / Accepted: 20 February 2020 © The Author(s) 2020
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. Keywords Corticospinal tract · Interleukin-4 · Growth-promoting treatment · Regeneration · Spinal cord injury
Introduction 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 equally contributed as first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-00820-7) contains supplementary material, which is available to authorized users. * Christina F. Vogelaar tineke.vogelaar@unimedizin‑mainz.de 1
Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
2
Institute for Developmental Biology and Neurobiology, Molecular Cell Biology, Johannes Gutenberg University Mainz, 55099 Mainz, Germany
3
University Medical Center, Institute for Translational Neuroscience, Westfälische Wilhelms-University Münster, Albert‑Schweitzer‑Campus, 48149 Münster, Germany
neuron-intrinsic as well as extrinsic factors in the lesioned spinal cord (Tedeschi and Bradke 2016; Vogelaar 2016). Not only growth-inhibitory molecules in and around the lesion are a barrier to axon regeneration, but also intrinsic regenerative responses, like the fast formation of a new growth cone and the activation of a regeneration program, are principally lacking in CNS neurons (Bradke et al. 2012; Chew et al. 2012; Mason et al. 2003; Verma et al. 2005; Vogel
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