Olfactory Ensheathing Cell Transplantation after a Complete Spinal Cord Transection Mediates Neuroprotective and Immunomodulatory Mechanisms to Facilitate Regeneration

Abstract

Multiple neural and peripheral cell types rapidly respond to tissue damage after spinal cord injury to form a structurally and chemically inhibitory scar that limits axon regeneration. Astrocytes form an astroglial scar and produce chondroitin sulfate proteoglycans (CSPGs), activate microglia, and recruit blood-derived immune cells to the lesion for debris removal. One beneficial therapy, olfactory ensheathing cell (OEC) transplantation, results in functional improvements and promotes axon regeneration after spinal cord injury. The lack of an OEC-specific marker, however, has limited the investigation of mechanisms underlying their proregenerative effects. We compared the effects of enhanced green fluorescent protein-labeled fibroblast (FB) and OEC transplants acutely after a complete low-thoracic spinal cord transection in adult rats. We assessed the preservation of neurons and serotonergic axons, the levels of inhibitory CSPGs and myelin debris, and the extent of immune cell activation between 1 and 8 weeks postinjury. Our findings indicate that OECs survive longer than FBs post-transplantation, preserve axons and neurons, and reduce inhibitory molecules in the lesion core. Additionally, we show that OECs limit immune-cell activation and infiltration, whereas FBs alter astroglial scar formation and increase immune-cell infiltration and concomitant secondary tissue damage. Administration of cyclosporine-A to enhance graft survival demonstrated that immune suppression can augment OEC contact-mediated protection of axons and neurons during the first 2 weeks postinjury. Collectively, these data suggest that OECs have neuroprotective and immunomodulatory mechanisms that create a supportive environment for neuronal survival and axon regeneration after spinal cord injury.

Brain-derived Neurotrophic Factor Promotes the Migration of Olfactory Ensheathing Cells Through TRPC Channels

“…6H. [Color figure can be viewed at wileyonlinelibrary.com] OEC transplantation has emerged as a very promising experimental therapy to treat the axonal injuries of central nervous system (Cao et al, 2004;Chiu et al, 2009;Khankan et al, 2016;Li et al, 1998;Mackay-Sim and St John, 2011;Raisman and Li, 2007;Ramon-Cueto et al, 1998;Su and He, 2010). (n 5 13, 16, 12, 9, 12, 8 cells in the indicated groups, respectively).…”

“…The [Ca 21 ] i was determined by the ratio of Fluo-4 and Flura-Red fluorescence. (C) Summary of average peak levels of Ca 21 signal based on the max [Ca 21 ] i signal from individual cells in the soma under various conditions (n 5 13, 16, 12, 9, 12, 8 cells OEC transplantation has emerged as a very promising experimental therapy to treat the axonal injuries of central nervous system (Cao et al, 2004;Chiu et al, 2009;Khankan et al, 2016;Li et al, 1998;Mackay-Sim and St John, 2011;Raisman and Li, 2007;Ramon-Cueto et al, 1998;Su and He, 2010). Organized migration of OECs enhances the axon regeneration (Chehrehasa et al, 2010;Ekberg et al, 2012;Windus et al, 2011).…”

The glial scar is more than just astrocytes

“…However, there do exist effective bridging techniques that have been used to span larger lesions (Houle et al, 2006;Alilain et al, 2011;Lee et al, 2013;Tabakow et al, 2014). Importantly, the addition of strategies that manipulate the astrocyte scar interface at the ends of the bridge and that take advantage of the plasticity of the reactive astrocyte must be employed to allow axons to regenerate not only into but well beyond the lesion Khankan et al, 2016). We have learned over the past decade or so that the glial scar is a lot more than just astrocytes and with this new knowledge our views about regeneration failure have evolved considerably (Cregg et al, 2014).…”

Rostro‐caudal maturation of glial cells in the accessory olfactory system during development: involvement in outgrowth of GnRH neurites

“…Mature OECs expressing the neurotrophin receptor p75 NTR have been shown to increase neurite outgrowth significantly in brain slices (Jiao et al ., ). It has also been suggested that mature OEC expressing p75 NTR increased the total neurites length of cortical neurones in culture by providing both an adhesive cellular substrate and permissive soluble factors (Khankan et al ., ). In line with our research, this latter study demonstrated a correlation between OEC process alignment with neurites and the size of neurite elongation, and it suggested that OEC process alignment was a method for OEC to enhanced neurites elongation/outgrowth.…”