Olfactory ensheathing cells promote neurite sprouting of injured axons in vitro by direct cellular contact and secretion of soluble factors

Abstract

Olfactory ensheathing cells (OECs) represent an exciting possibility for promoting axonal regeneration within the injured spinal cord. A number of studies have indicated the ability of these cells to promote significant reactive sprouting of injured axons within the injured spinal cord, and in some cases restoration of functional abilities. However, the cellular and/or molecular mechanisms OECs use to achieve this are unclear. To investigate such mechanisms, we report for the first time the ability of OECs to promote post-injury neurite sprouting in an in vitro model of axonal injury. Using this model, we were able to differentiate between the direct and indirect mechanisms underlying the ability of OECs to promote neuronal recovery from injury. We noted that OECs appeared to act as a physical substrate for the growth of post-injury neurite sprouts. We also found that while post-injury sprouting was promoted most when OECs were allowed to directly contact injured neurons, physical separation using tissue culture inserts (1 mm pore size, permeable to diffusible factors but not cells) did not completely block the promoting properties of OECs, suggesting that they also secrete soluble factors which aid post-injury neurite sprouting. Furthermore, this in vitro model allowed direct observation of the cellular interactions between OECs and sprouting neurites using live-cell-imaging techniques. In summary, we found that OECs separately promote neurite sprouting by providing a physical substrate for growth and through the expression of soluble factors. Our findings provide new insight into the ability of OECs to promote axonal regeneration, and also indicate potential targets for manipulation of these cells to enhance their restorative ability.

Genes Associated with Adult Axon Regeneration Promoted by Olfactory Ensheathing Cells: A New Role for Matrix Metalloproteinase 2

“…and West, 2002;Moreno-Flores et al, 2002;Chung et al, 2004). Our functional genomic study supports this hypothesis and goes one step further, for the first time identifying candidate genes.…”

“…It seems likely that their influence on regeneration will depend on the orchestrated activity of secreted factors, membrane-bound molecules, and extracellular matrix components. The cooperation of these factors will first promote the survival of axotomized neurons and then aid them to regenerate their axons (Moreno-Flores et al, 2002;Chung et al, 2004).…”

SPARC from Olfactory Ensheathing Cells Stimulates Schwann Cells to Promote Neurite Outgrowth and Enhances Spinal Cord Repair

“…We previously demonstrated significant sensory axon sprouting in response to transplanted LPOECs in vivo, a response that may require tight regulation to maximize desired and minimize undesired regeneration (that may lead to neuropathic pain) after lesion (Ramer et al, 2004b;Richter et al, 2005). OEC activity is attributed, in part, to secreted factors (Kafitz and Greer, 1999;Chung et al, 2004). Here, we selected a well established model of sensory outgrowth and guidance E13.5 mouse DRG explants, to elucidate the mechanisms whereby LP-OECs promote neurite outgrowth.…”

“…Although OEC migration is highly limited within the lesioned spinal cord, a variety of responses distant from the site of transplantation Ramer et al, 2004b) suggest that OECs may secrete factors that can stimulate more widespread repair after transplantation (Kafitz and Greer, 1999;Chung et al, 2004). The simple observation that OECs significantly lose their potential to promote neurite outgrowth as they age enabled us to use differential proteomics to test which secreted factors may be responsible for this activity.…”

Transplanted Olfactory Ensheathing Cells Reduce Retinal Degeneration in Royal College of Surgeons Rats

“…and bFGF 28) that the OECs/ONFs mixtures secrete an array of neurotrophic factors which may be significant in maintaining the survival of the photoreceptors.…”