Axonal Thinning and Extensive Remyelination without Chronic Demyelination in Spinal Injured Rats

Abstract

Remyelination following spinal cord injury (SCI) is thought to be incomplete; demyelination is reported to persist chronically and is proposed as a compelling therapeutic target. Yet most reports do not distinguish between the myelin status of intact axons and injury-severed axons whose proximal stumps persist but provide no meaningful function. We previously found full remyelination of spared, intact rubrospinal axons caudal to the lesion in chronic mouse SCI. However, the clinical concept of chronically demyelinated spared axons remains controversial. Since mouse models may have limitations in clinical translation, we asked whether the capacity for full remyelination is conserved in clinically relevant chronic rat SCI. We determined myelin status by examining paranodal protein distribution on anterogradely labeled, intact corticospinal and rubrospinal axons throughout the extent of the lesion. Demyelination was evident on proximal stumps of severed axons, but not on intact axons. For the first time, we demonstrate that a majority of intact axons exhibit remyelination (at least one abnormally short internode, < 100 μm). Remarkably, shortened internodes were significantly concentrated at the lesion epicenter and individual axons were thinned by 23% compared to their rostral and caudal zones. Mathematical modeling predicted a 25% decrease in conduction velocity at the lesion epicenter due to short internodes and axonal thinning. In conclusion, we do not find a large chronically demyelinated population to target with remyelination therapies. Interventions may be better focused on correcting structural or molecular abnormalities of regenerated myelin.

Epicritic Sensation in Cervical Spinal Cord Injury: Diagnostic Gains Beyond Testing Light Touch

“…In addition, such measures might be useful if interventions are considered to improve the myelination (i.e., concept of re-myelination) of damaged spinal fibers, where the recovery of A-b fibers depend on high level of myelination and might reveal superior recovery than less or unmyelinated sensory fibers (such as C fibers). 31,32 Therefore, in clinical trials, an improved resolution of sensory function by combined LT and SWM/EPT testing could be meaningful in revealing subtle changes that, for a proof of mechanism, might be critical for entering a next phase in which these effects can be amplified by adjusting the intervention.…”

Sonic hedgehog and neurotrophin-3 increase oligodendrocyte numbers and myelination after spinal cord injury

“…Following injury, myelinating cells in the spinal cord consist of Schwann cells and oligodendrocytes. Schwann cells from the peripheral nervous system (PNS) rapidly invade the spinal cord after injury and can spontaneously remyelinate spared axons in the central nervous system (CNS); however, Schwann cells generally do not form myelin sheaths thick enough to restore axonal conductance 6,7 . In contrast, oligodendrocytes, which normally produce myelin in the CNS, can myelinate multiple spared axons to enhance and integrate their conductance 8 .…”

Does the preclinical evidence for functional remyelination following myelinating cell engraftment into the injured spinal cord support progression to clinical trials?

“…Here and throughout this review, we use a less rigorous definition of the term ‘remyelination’ to indicate any increase in the remyelination of demyelinated axons, myelination of newly sprouted axons, or the sparing of existing, myelinated axons. Short of anterograde tracing spared axons and quantifying myelinating cells (Powers et al, 2012), traditional methods of quantifying myelinating cells cannot exclude these possibilities.…”

“…There is universal agreement that oligodendrocyte loss after spinal cord injury (SCI) results in acute demyelination, both in experimental animals (Blight, 1983; Cao et al, 2005b; Crowe et al, 1997; Gledhill et al, 1973; Hesp et al, 2015; Powers et al, 2012; Totoiu and Keirstead, 2005) and humans (Guest et al, 2005; Kakulas, 1999; Norenberg et al, 2004). There is, however, conflicting evidence in experimental SCI as to whether chronic demyelination is a component of the long term pathophysiology.…”

“…Early studies suggested chronic demyelination after SCI is relevant (Blight, 1983; Totoiu and Keirstead, 2005). More recent studies showed little evidence of demyelinated axons, but rather extensive ongoing remyelination (Hesp et al, 2015; Powers et al, 2012). Human pathological studies similarly do not show substantial evidence of chronic demyelination (Norenberg et al, 2004), although some was noted in a few cases 10 years post-SCI (Guest et al, 2005).…”