Neurorehabilitation and white matter repair in traumatic spinal cord injury: a dialogue between clinical and preclinical studies

The central nervous system (CNS) has very limited repair capabilities, and the functional adaptation/compensation after acute injuries is attributed to the significant plasticity of neural circuits, in particular at the synaptic level. However, neurons are only one of the cellular components of the CNS, with gray matter (GM) comprising around 50% of its structure, compared to white matter (WM), where oligodendrocytes (Ols) form the myelin sheath and ensure the isolation of axons for proper electrical conductivity elicited by action potentials. WM is characterized by two remarkable properties: myelin plasticity, defined as experience-induced changes in myelination that mediate long-lasting changes in neural circuit function, and myelin repair, which can be complete and functionally effective and represents the CNS's only true reparative capability. Oligodendrocyte precursor cells (OPCs), accounting for 5–8% of the total CNS cells, are responsible for myelin plasticity and repair. OPCs are generated during development, are widely distributed across both white and gray matter, and remain quiescent until appropriate stimuli, such as functional requests or injuries, arise. Under these conditions, endogenous OPCs, as well as new OPCs derived from the proliferation and differentiation of endogenous neural stem cells, migrate toward axons and differentiate into mature OLs capable of wrapping axons and forming the myelin sheaths. In this review article, we discuss WM plasticity and myelin repair through OPC-dependent endogenous regeneration within the context of spinal cord injury (SCI) and related neurorehabilitation approaches. Clinical data, such as imaging information, pertain to changes in WM during various phases of SCI and have been collected in different rehabilitation contexts. Preclinical data focus on physical stimuli that can enhance the myelin repair capacity of OPCs within the context of the oligo-axon unit. The potential role of myelin regeneration by endogenous stem/precursor cells is finally discussed in the context of regenerative neurorehabilitation for SCI.