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Target-specific regeneration in the mouse spinal cord




The widely known research groups led by Swiss neuroscientists Gregoire Courtine and Mark Anderson have already shown in earlier studies that it is possible to regenerate axons across complete spinal cord lesions. However, the laboratory from Lausanne has so far failed to prove to the scientific community that a substantial recovery of function can also take place.


In a recent publication, Jordan W. Squair and colleagues have now examined axons of a very specific group of neurons which, after special treatment, reactivate their pre-lesion innervated target neurons in the lumbar spinal cord of mice. These data, published in the renowned journal Science, are presented today in my blog by medical student Leander Julius Ruchti.


The researchers around Courtine and Anderson first used retrograde fluorescence labeling to identify a specific group of nerve cells in the thoracic spinal cord that innervate lumbar motor neurons. After single-cell RNA sequencing, the homeobox transcription factors Vsx2 and Zfhx3 were detected in some of these cells. Zfhx3 is a marker that indicates axonal projections over a longer distance, while Vsx2 is particularly expressed in defined projection neurons of the motor system during development. Apparently, however, these neurons are not directly involved in walking in the uninjured mouse, but are in a kind of waiting or resting position.


By applying chemoattractive factors and reactivating intrinsic neuronal growth programs, a pronounced axonal regeneration across a complete spinal cord injury had already been demonstrated in earlier studies. However, as there was no functional recovery, the scientists led by Jordan W. Squair applied additional GDNF depots to the lumbar spinal cord and also used lentivirus-based systems to provide GDNF permanently by means of gene therapy.


In addition, they reactivated the intrinsic growth capacity of neurons above the lesion by overexpressing osteopontin, insulin-like growth factor 1 (IGF1) and ciliary neurotrophic factor (CNTF). Furthermore, the formation of growth-promoting substrates in the area of the lesion was promoted by delayed administration of fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF).


Both, fluorescence labeling and functional analysis of the treated mice showed pronounced axonal regeneration with restoration of motor function. The specificity of the approach was demonstrated by stimulating supraspinal neurons in the formatio reticularis, which innervate thoracic Vsx2/Zfhx3-positive spinal cord neurons, and thereby triggering electrical potentials in the leg muscles.


Walking tests showed a good recovery of walking function, which was absent after chemical ablation of the regenerated Vsx2/Zfhx3-positive neurons. This also proved that this particular thoracic neuron group is crucial for regeneration after spinal cord lesions and that other nerve cells do not take over the task.


However, despite the methodological sophistication and impressive functional results, it remains to be seen whether the neuronal projection demonstrated in mice is also present in humans and could actually restore stepping motor function after a spinal cord injury and specific regeneration.

Reference:


Squair JW, Milano M, de Coucy A, ..., He Z, Bloch J, Sofroniew MV, Courtine G, Anderson MA (2023) Recovery of walking after paralysis by regenerating characterized neurons to their natural target region. Science 381:1338


Image credit: iStock/Firstsignal

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