Abstract
BackgroundAfter spinal cord injury (SCI), the formation of glial scar contributes to the failure of injured adult axons to regenerate past the lesion. Increasing evidence indicates that olfactory ensheathing cells (OECs) implanted into spinal cord are found to migrate into the lesion site and induce axons regeneration beyond glial scar and resumption of functions. However, little is known about the mechanisms of OECs migrating from injection site to glial scar/lesion site.Methods and FindingsIn the present study, we identified a link between OECs migration and reactive astrocytes in glial scar that was mediated by the tumor necrosis factor-α (TNF-α). Initially, the Boyden chamber migration assay showed that both glial scar tissue and reactive astrocyte-conditioned medium promoted OECs migration in vitro. Reactive astrocyte-derived TNF-α and its type 1 receptor TNFR1 expressed on OECs were identified to be responsible for the promoting effect on OECs migration. TNF-α-induced OECs migration was demonstrated depending on activation of the extracellular signal-regulated kinase (ERK) signaling cascades. Furthermore, TNF-α secreted by reactive astrocytes in glial scar was also showed to attract OECs migration in a spinal cord hemisection injury model of rat.ConclusionsThese findings showed that TNF-α was released by reactive astrocytes in glial scar and attracted OECs migration by interacting with TNFR1 expressed on OECs via regulation of ERK signaling. This migration-attracting effect of reactive astrocytes on OECs may suggest a mechanism for guiding OECs migration into glial scar, which is crucial for OECs-mediated axons regrowth beyond the spinal cord lesion site.
Highlights
Damage to adult mammalian central nervous system (CNS) leads to persistent functional deficits for the lack of axonal regeneration and reconnection with correct synaptic targets
These findings showed that tumor necrosis factor-a (TNF-a) was released by reactive astrocytes in glial scar and attracted olfactory ensheathing cells (OECs) migration by interacting with TNFR1 expressed on OECs via regulation of extracellular signalregulated kinase (ERK) signaling
This migration-attracting effect of reactive astrocytes on OECs may suggest a mechanism for guiding OECs migration into glial scar, which is crucial for OECsmediated axons regrowth beyond the spinal cord lesion site
Summary
Damage to adult mammalian central nervous system (CNS) leads to persistent functional deficits for the lack of axonal regeneration and reconnection with correct synaptic targets. The glial scar which composed primarily of reactive astrocytes has long been implicated as a major impediment to axon regeneration and functional outcome after SCI and other forms of CNS injury [2,3]. It constitutes a mechanical obstacle and a biochemical barrier to preventing successful regeneration, as several classes of growth inhibitory molecules are upregulated and have been shown to contribute to the failure of axon regeneration [2,4,5,6]. Increasing evidence indicates that olfactory ensheathing cells (OECs) implanted into spinal cord are found to migrate into the lesion site and induce axons regeneration beyond glial scar and resumption of functions. Little is known about the mechanisms of OECs migrating from injection site to glial scar/lesion site
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