Patients of neurodegenerative diseases such as Alzheimer and Parkinson as well as people that suffer spinal cord injuries would surely benefit if we would manage to enhance somehow the very limited regenerative capacities of our central nervous system. But whereas mammals show almost no regeneration potential in their CNS, other vertebrates such as amphibians and zebrafish are capable of regenerating their spinal cord. Also, invertebrates such as planarians can regenerate a complete CNS de novo from any small piece of their bodies. So, how do amphibians and fish do to regenerate their spinal cord? What prevents mammals from doing the same? Because of the great potential benefits of enhancing mammalian CNS regeneration a lot of research is being done in this field; however, the results are not being really very promising yet, at least as fast as demanded by the society.
In a recent review from the laboratory of Karen Echeverri the authors discuss the current state-of-the-art of vertebrate CNS regeneration (http://www.ncbi.nlm.nih.gov/pubmed/23581406). When comparing the regenerative response of mammals to that from amphibians and fish important aspects that need to be considered include the cellular response to injuries and the formation and role of the glial scar. In zebrafish, upon injury, glial cells amplify and migrate to the lesion where they elongate creating a glial bridge that axons use as a scaffold to grow across the lesion. A very interesting observation in zebrafish is that the re-wiring of the regenerated CNS does not need to be one hundred per cent accurate (in terms of re-establishing the original connections) to yield a functional recovery.
Amphibians, both anurans (tailless amphibians) and urodeles (tailed amphibians) regenerate the spinal cord during tail regeneration. In Xenopus it has been described a population of putative neural stem cells positive for Sox-2 that, upon injury, proliferate and migrate forming a substrate for axonal regeneration. In urodeles, also, fibroblasts and glial cells migrate to create a substrate for axonal regeneration. Thus, in all these models once the spinal cord is injured certain cell types are able to create a regeneration-permissive environment. Another thing that is shared by amphibians and zebrafish refers to the upregulation of signalling pathways such as Wnt, BMP and FGF during spinal cord regeneration.
In contrast, CNS regeneration in mammals is inhibited by both extrinsic and intrinsic factors. One of the most important inhibitors is the glial scar that acts as a physical and chemical barrier to regeneration. In zebrafish and amphibians, however, no inhibitory glial scar is formed. Recently it is emerging the view that in mammals the glial scar although inhibiting axonal regeneration may have an important role as a protective agent during early stages after injury. In this sense it becomes interesting to further analyse whether the inhibitory action of the glial scar on regeneration is an unavoidable trade-off of its beneficial role on stabilizing the injury site preventing further damage. If this is true maybe it means that there is a kind of evolutionary constraint that really works against the possibility of enhancing CNS regeneration in mammals. Another field to develop is the study of the inhibitory action on regeneration by myelin components such us Nogo, myelin-associated protein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp). Different studies have shown contradictory results in terms of enhancing the regenerative capabilities after inhibiting these factors. Therefore more data and comparative analyses are needed from animals that can and cannot regenerate their CNS.
In summary, and as it has been pointed out in previous posts on this blog, it is important not only to understand as deeply as possible how regeneration takes place at both cellular and molecular level, but also to try to determine why the regeneration potential has been lost in certain lineages. In this sense spinal cord regeneration provides with a very attractive model in which direct comparisons between regenerating and non-regenerating models (phylogenetically close, such as amphibians, fish and mammals) can be beneficial for the field as it may help, for example, to determine what really makes that some species are able to create a regeneration-permissive environment whereas others, in which similar cell types and molecular pathways are present and even upregulated after injury, cannot do it.