From demyelination to remyelination: The road toward therapies for spinal cord injury

Abstract

Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation.

Transcranial magnetic motor evoked potentials and magnetic resonance imaging findings in paraplegic dogs with recovery of motor function

“…As in the present study, only dogs presenting acute severe motor function impairment due to a different pathogenesis were enrolled, the differences of CLR, T2W‐LER, and T2WLR values between Grade IV and V could be too low to detect a significant correlation with TMMEPs during therapy monitoring. A correlation of MRI measurements and TMMEPs both obtained at 2nd follow‐up examination was not expected, because absence of compression and persistence of focal spinal cord hyperintensities do not reflect microstructural processes, which contribute to functional motor recovery …”

“…Remyelination arises from resident glial progenitor cells, infiltrating the injured region, where they differentiate into oligodendrocytes producing myelin . Additionally, PNS associated Schwann cells migrate to the spinal cord lesion, contributing to remyelination by expressing platelet derived growth factor receptor α . These processes start immediately after injury.…”

New Aspects of Graft-induced Central Plasticity and Neuroregeneration at T 10 in a Rat Model†

“…Until now, traumatic paraplegia by severance of the spinal cord (SC) remains an irreversible condition. Basically, current clinical treatment strategies are targeted to promote axon regeneration and outgrowth beyond the scar formation following SC avulsion [1][2][3][4][5][8][9][10][11][12][13][14][15][16][17][18][20][21][24][25][26][27][28][29][30][31][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Previous experimental and clinical studies together with GB have aroused some hope that paraplegic patients might achieve some selective voluntary muscle reinnervation after grafting the first motor neuron to skeletal hip muscles [10,11,25,72,73].…”

Regeneration of myelin sheaths of normal length and thickness in the zebrafish CNS correlates with growth of axons in caliber

“…Demyelination occurs secondarily following spinal cord injuries [23], and although remyelination can occur on spared axons, it is insufficient to fully restore function [24]. In recent years a number of intrinsic and extrinsic factors have been identified that can influence remyelination efficiency, offering the possibility to use this knowledge to develop therapeutic interventions [25].…”