Long-Distance Axonal Regeneration in the Transected Adult Rat Spinal Cord Is Promoted by Olfactory Ensheathing Glia Transplants

Abstract

The lack of axonal regeneration in the injured adult mammalian spinal cord leads to permanent functional impairment. To induce axonal regeneration in the transected adult rat spinal cord, we have used the axonal growth-promoting properties of adult olfactory bulb ensheathing glia (EG). Schwann cell (SC)-filled guidance channels were grafted to bridge both cord stumps, and suspensions of pure (98%) Hoechst-labeled EG were stereotaxically injected into the midline of both stumps, 1 mm from the edges of the channel. In EG-transplanted animals, numerous neurofilament-, GAP-43-, anti-calcitonin generelated peptide (CGRP)-, and serotonin-immunoreactive fibers traversed the glial scars formed at both cord-graft interfaces. Supraspinal serotonergic axons crossed the transection gap through connective tissue bridges formed on the exterior of the channels, avoiding the channel interior. Strikingly, after crossing the distal glial scar, these fibers elongated in white and periaqueductal gray matter, reaching the farthest distance analyzed (1.5 cm). Tracer-labeled axons present in SC grafts were found to extend across the distal interface and up to 800 m beyond in the distal cord. Long-distance regeneration (at least 2.5 cm) of injured ascending propriospinal axons was observed in the rostral spinal cord. Transplanted EG migrated longitudinally and laterally from the injection sites, reaching the farthest distance analyzed (1.5 cm). They moved through white matter tracts, gray matter, and glial scars, overcoming the inhibitory nature of the CNS environment, and invaded SC and connective tissue bridges and the dorsal and ventral roots adjacent to the transection site. Transplanted EG and regenerating axons were found in the same locations. Because EG seem to provide injured spinal axons with appropriate factors for long-distance elongation, these cells offer new possibilities for treatment of CNS conditions that require axonal regeneration.

Migratory properties of cultured olfactory ensheathing cells by single-cell migration assay

“…Owing to these unique roles, OEC transplantation has emerged as a promising experimental therapy for axonal injuries and demyelinating disease [5]. Experimental studies have shown that OECs transplanted near nerve injury sites can not only promote the re-growth of injured axons [6][7][8], but also form myelin sheaths around demyelinated axons, leading to the restoration of axonal functions [9][10][11][12][13][14][15]. Moreover, transplantation of autologous OECs into the injured spinal cord in human is feasible and is safe up to 1 year after implantation [16].…”

Transplantation Options for Therapeutic Central Nervous System Remyelination

“…Myelin sheaths made by transplanted glial cells en hance action potential conduction (20,21,39) and we have been able to show that both normal and transplantmediated remyelination results in restoration of function lost as a consequence of demyelination (22). In addition, Schwann cell and olfactory ensheathing cell transplanta tion, in the form of "bridges," provides a means of stim ulating regeneration of CNS axons (19,32). Glial cell transplantation may therefore provide a therapeutic strat egy for remyelinating areas of chronic demyelination and stimulating axon regeneration.…”

The Immunohistochemical Characterization of Human Fetal Olfactory Bulb and Olfactory Ensheathing Cells in Culture as a Source for Clinical CNS Restoration

“…Since olfactory ensheathing cells (OECs) have been reported to enhance axonal regeneration in rat spinal cord when transplanted into lesion sites (Li et al, 1997;Ramon-Cueto et al, 1998), OECs have become a prime candidate for cell-mediated repair following a variety of Central Nervous System (CNS) lesions (Richter and Roskams, 2008) not only in animal model but also in clinical situation (Li et al, 1998;Dobkin et al, 2006;Franssen et al, 2007;Bauchet et al, 2008). More and more literature reviews give us more and more hope that OEC transplantation to be one of the most promising therapeutic strategies (Barnett and Riddell, 2007;Sasaki et al, 2007;Bauchet et al, 2008;Bunge, 2008;Radtke et al, 2008;Richter and Roskams, 2008;Kawaja et al, 2009); OECs have been successfully transplanted in acute (Resnick et al, 2003;Polentes et al, 2004;Collazos-Castro et al, 2005;Lopez-Vales et al, 2006;Andrews and Stelzner, 2007;Sasaki et al, 2007) and chronic (Andrews and Stelzner, 2004;Lopez-Vales et al, 2007) models of rodent spinal cord injury.…”