Descending propriospinal neurons (DPSN) are known to establish functional relays for supraspinal signals, and they display a greater growth response after injury than do the long projecting axons. However, their regenerative response is still deficient due to their failure to depart from growth supportive cellular transplants back into the host spinal cord, which contains numerous impediments to axon growth. Here we report the construction of a continuous growth-promoting pathway in adult rats, formed by grafted Schwann cells (SCs) overexpressing glial cell line-derived neurotrophic factor (GDNF). We demonstrate that such a growth-promoting pathway, extending from the axonal cut ends to the site of innervation in the distal spinal cord, promoted regeneration of DPSN axons through and beyond the lesion gap of a spinal cord hemisection. Within the distal host spinal cord, regenerated DPSN axons formed synapses with host neurons leading to the restoration of action potentials and partial recovery of function.

ObjectiveThe objective of this study was to investigate whether cytosolic phospholipase A2 (cPLA2), an important isoform of PLA2 that mediates the release of arachidonic acid, plays a role in the pathogenesis of spinal cord injury (SCI).MethodsA combination of molecular, histological, immunohistochemical, and behavioral assessments were used to test whether blocking cPLA2 activation pharmacologically or genetically reduced cell death, protected spinal cord tissue, and improved behavioral recovery after a contusive SCI performed at the 10th thoracic level in adult mice.ResultsSCI significantly increased cPLA2 expression and activation. Activated cPLA2 was localized mainly in neurons and oligodendrocytes. Notably, the SCI-induced cPLA2 activation was mediated by the extracellular signal-regulated kinase signaling pathway. In vitro, activation of cPLA2 by ceramide-1-phosphate or A23187 induced spinal neuronal death, which was substantially reversed by arachidonyl trifluoromethyl ketone, a cPLA2 inhibitor. Remarkably, blocking cPLA2 pharmacologically at 30 minutes postinjury or genetically deleting cPLA2 in mice ameliorated motor deficits, and reduced cell loss and tissue damage after SCI.InterpretationcPLA2 may play a key role in the pathogenesis of SCI, at least in the C57BL/6 mouse, and as such could be an attractive therapeutic target for ameliorating secondary tissue damage and promoting recovery of function after SCI.

Reactive astrogliosis has been considered as a major impediment for axonal regeneration after injuries in the mammalian central nervous system (CNS). Here we report that glial cell linederived neurotrophic factor (GDNF), combined with transplanted Schwann cells (SCs), effectively reversed the inhibitory properties of astrocytes at graft-host interfaces allowing robust axonal regeneration, concomitant with vigorous migration of host astrocytes, into SC-seeded semipermeable guidance channels implanted into a right-sided spinal cord hemisection at the 10 th thoracic (T10) level. Within the graft, migrated host astrocytes were in close association with regenerated axons with their processes extended parallel to the axons, implying that the migrated astrocytes were not inhibitory and might have promoted directional growth of regenerated axons. In vitro, GDNF induced migration of SCs and astrocytes toward each other in an astrocyte-SC confrontation assay. GDNF also enhanced migration of astrocytes on a SC monolayer in an inverted coverslip migration assay, suggesting that this effect is mediated by a direct cell-cell contact between the two cell types. Morphologically, GDNF administration reduced astrocyte hypertrophy and induced elongated process extension of these cells, similar to what was observed in vivo. Notably, GDNF treatment significantly reduced production of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs), two hallmarks of astrogliosis, in both the in vivo and in vitro models. Thus, our study has demonstrated, for the first time, a novel role and mechanism of GDNF on modification of spinal cord injury (SCI)-induced astrogliosis resulting in robust axonal regeneration in adult rats.

Oligodendrocyte (OL) replacement can be a promising strategy for spinal cord injury (SCI) repair. However, the poor posttransplantation survival and inhibitory properties to axonal regeneration are two major challenges that limit their use as donor cells for repair of CNS injuries. Therefore, strategies aimed at enhancing the survival of grafted oligodendrocytes as well as reducing their inhibitory properties, such as the use of more permissive oligodendrocyte progenitor cells (OPCs), also called glial restricted precursor cells (GRPs), should be highly prioritized. Schwann cell (SC) transplantation is a promising translational strategy to promote axonal regeneration after CNS injuries, partly due to their expression and secretion of multiple growth-promoting factors. Whether grafted SCs have any effect on the biological properties of grafted GRPs remains unclear. Here we report that either SCs or SC-conditioned medium (SCM) promoted the survival, proliferation, and migration of GRPs in vitro. When GRPs and SCs were cografted into the normal or injured spinal cord, robust survival, proliferation, and migration of grafted GRPs were observed. Importantly, grafted GRPs differentiated into mature oligodendrocytes and formed new myelin on axons caudal to the injury. Finally, cografts of GRPs and SCs promoted recovery of function following SCI. We conclude that cotransplantation of GRPs and SCs, the only two kinds of myelin-forming cells in the nervous system, act complementarily and synergistically to promote greater anatomical and functional recovery after SCI than when either cell type is used alone.

After spinal cord injury (SCI), poor ability of damaged axons of the central nervous system (CNS) to regenerate causes very limited functional recovery. Schwann cells (SCs) have been widely explored as promising donors for transplantation to promote axonal regeneration in the CNS including the spinal cord. Compared with other CNS axonal pathways, injured propriospinal tracts display the strongest regenerative response to SC transplantation. Even without providing additional neurotrophic factors, propriospinal axons can grow into the SC environment which is rarely seen in supraspinal tracts. Propriospinal tract has been found to respond to several important neurotrophic factors secreted by SCs. Therefore, the SC is considered to be one of the most promising candidates for cell-based therapies for SCI. Since many reviews have already appeared on topics of SC transplantation in SCI repair, this review will focus particularly on the rationale of SC transplantation in mediating descending propriospinal axonal regeneration as well as optimizing such regeneration by using different combinatorial strategies.

Although lipid peroxidation has long been associated with spinal cord injury (SCI), the specific role of lipid peroxidation-derived byproducts such as acrolein in mediating damage remains to be fully understood. Acrolein, an α-β unsaturated aldehyde, is highly reactive with proteins, DNA, and phospholipids and is considered as a second toxic messenger that disseminates and augments initial free radical events. Previously, we showed that acrolein increased following traumatic SCI and injection of acrolein induced tissue damage. Here, we demonstrate that microinjection of acrolein into the thoracic spinal cord of adult rats resulted in dose-dependent tissue damage and functional deficits. At 24 hours (acute) after the microinjection, tissue damage, motoneuron loss, and spinal cord swelling were observed on sections stained with cresyl violet. Luxol fast blue staining further showed that acrolein injection resulted in dose-dependent demyelination. At 8 weeks (chronic) after the microinjection, cord shrinkage, astrocyte activation, and macrophage infiltration were observed along with tissue damage, neuron loss, and demyelination. These pathological changes resulted in behavioral impairments as measured by both the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and grid walking analysis. Electron microscopy further demonstrated that acrolein induced axonal degeneration, demyelination, and macrophage infiltration. These results, combined with our previous reports, strongly suggest that acrolein may play a critical causal role in the pathogenesis of SCI and that targeting acrolein could be an attractive strategy for repair after SCI.