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Enhancing CNS Repair in Neurological Disease

Challenges Arising from Neurodegeneration and Rewiring of the Network

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Abstract

Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies. By taking spinal cord injury, cerebral ischaemia and degenerative CNS disorders as examples for CNS repair, we discuss progress and potential problems in utilizing embryonic stem cells and adult neural/non-neural stem cells to repair cell loss in the CNS. Nevertheless, CNS repair is not simply a matter of cell transplantation. The major challenge is to induce regenerating neural cells to integrate into the neural network and compensate for damaged neural function. The neural cells confront an environment very different from that of the developmental stage in which these cells differentiate to form interwoven networks.

During the repair process, one of the challenges is neurodegeneration, which can develop from interrupted innervations to/from the targets, chronic inflammation, ischaemia, aging or idiopathic neural toxicity. Neurodegeneration, which occurs on the basis of a characteristic vascular and neural web, usually presents as a chronically progressive process with unknown aetiology. Currently, there is no effective treatment to stop or slow down neurodegeneration. Pathological changes from patients with Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis indicate a broken homeostasis in the CNS. We discuss how the blood-brain barrier and neural networks are formed to maintain CNS homeostasis and their contribution to neurodegeneration in diseased conditions.

Another challenge is that some inhibitors produced by CNS injury do not facilitate the regenerating neural cells to incorporate into a pre-existing network. We review glial responses to CNS injury. Of note, the reactive astrocytes not only encompass the lesions/pathogens but may also form glial scars to impede regenerating axons from traversing the lesions. In addition, myelin debris can prevent axon growth. Myelination enables saltatory transduction of electrical impulses along axonal calibers and actually provides trophic support to stabilize the axons. Therefore, repair strategies should be designed to promote axonal growth, myelination and modulate astrocytic responses. Finally, we discuss recent progress in developing human monoclonal IgMs that regulate CNS homeostasis and promote neural regeneration.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (R01 GM092993, R01 NS024180, R01 NS032129, R01 NS048357 and R21 NS073684) and the National Multiple Sclerosis Society (CA 1060A11). This work was also supported by a grant from the NIH CTSA (Center for Translational Science Activities - HIPFA). We also acknowledge with thanks support from the Applebaum, Hilton and Peterson Foundations and the Minnesota Partnership for Biotechnology and Medical Genomics. Patents for antibodies that promote remyelination and CNS repair are issued and owned by the Mayo Foundation. Therefore, the authors have a potential future financial conflict of interest. Dr Warrington also owns stock in Acorda Therapeutic Inc. We thank Lea Dacy for helping to edit the manuscript.

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Authors and Affiliations

  1. Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

    Xiaohua Xu, Arthur E. Warrington, Allan J. Bieber & Moses Rodriguez (MD)

  2. Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota, USA

    Moses Rodriguez (MD)

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  1. Xiaohua Xu
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  2. Arthur E. Warrington
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  3. Allan J. Bieber
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  4. Moses Rodriguez
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Correspondence to Moses Rodriguez.

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Xu, X., Warrington, A.E., Bieber, A.J. et al. Enhancing CNS Repair in Neurological Disease. CNS Drugs 25, 555–573 (2011). https://doi.org/10.2165/11587830-000000000-00000

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