Olfactory ensheathing glia and spinal cord injury: basic mechanisms to transplantation (original) (raw)
Related papers
Experimental Neurology, 2011
Olfactory ensheathing cells (OECs) have been investigated extensively as a therapy to promote repair in the injured CNS, with variable efficacy in numerous studies over the previous decade. In many studies that report anatomical and functional recovery, the beneficial effects have been attributed to the ability of OECs to cross the PNS-CNS boundary, their production of growth factors, cell adhesion molecules and extracellular matrix proteins that promote and guide axon growth, and their ability to remyelinate axons. In this brief review, we focus on the interaction between OECs and astrocytes in vivo and in vitro, in the context of how OECs may be overcoming the deleterious effects of the glial scar. Drawing from a selection of different experimental models of spinal injury, we discuss the morphological alterations of the glial scar associated with OEC transplants, and the in vitro research that has begun to elucidate the interaction between OECs and the cell types that compose the glial scar. We also discuss recent research showing that OECs bear properties of immune cells and the consequent implication that they may modulate neuroinflammation when transplanted into CNS injury sites. Future studies in unraveling the molecular interaction between OECs and other glial cells may help explain some of the variability in outcomes when OECs are used as transplants in CNS injury and more importantly, contribute to the optimization of OECs as a cell-based therapy for CNS injury. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.
Neuroscience letters, 2009
Olfactory ensheathing cells (OECs) are specialized glial cells that guide olfactory receptor axons from the nasal mucosa into the brain where they make synaptic contacts in the olfactory bulb. While a number of studies have demonstrated that in vivo transplantation of OECs into injured spinal cord results in improved functional outcome, precise cellular mechanisms underlying this improvement are not fully understood. Current thinking is that OECs can encourage axonal regeneration, provide trophic support for injured neurons and for angiogenesis, and remyelinate axons. However, Schwann cell (SC) transplantation also results in significant functional improvement in animal models of spinal cord injury. In culture SCs and OECs share a number of phenotypic properties such as expression of the low affinity NGF receptor (p75). An important area of research has been to distinguish potential differences in the in vivo behavior of OECs and SCs to determine if one cell type may offer greater a...
Olfactory Ensheathing Glia: Drivers of Axonal Regeneration in the Central Nervous System?
Journal of Biomedicine and Biotechnology, 2002
Olfactory ensheathing glia (OEG) accompany olfactory growing axons in their entry to the adult mammalian central nervous system (CNS). Due to this special characteristic, considerable attention has been focused on the possibility of using OEG for CNS regeneration. OEG present a large heterogeneity in culture with respect to their cellular morphology and expressed molecules. The specific characteristics of OEG responsible for their regenerative properties have to be defined. These properties probably result from the combination of several factors: molecular composition of the membrane (expressing adhesion molecules as PSA-NCAM, L1 and/or others) combined with their ability to reduce glial scarring and to accompany new growing axons into the host CNS. Their capacity to produce some neurotrophic factors might also account for their ability to produce CNS regeneration.
Potential of olfactory ensheathing cells for cell-based therapy in spinal cord injury
Journal of Rehabilitation Research and Development, 2008
Contusive spinal cord injury (SCI) results in a complex lesion that includes cellular and axonal loss, microglia and macrophage activation, and demyelination. These changes result in permanent neurological deficits in people with SCI and in high financial costs to society. Unlike the peripheral nervous system (PNS), in which axonal regeneration can occur, axonal regeneration in the central nervous system (CNS) is extremely limited. This limited regeneration is thought to result from a lack of a permissive environment and from active inhibitory molecules that are present in the CNS but minimal in the PNS. Currently, cell transplantation approaches are among several experimental strategies being investigated for the treatment of SCI. In the olfactory system, a specialized glial cell called the olfactory ensheathing cell (OEC) has been shown to improve functional outcome when transplanted into rodents with SCI, and clinical studies transplanting OECs into patients with SCI are ongoing in China, Portugal, and other sites. Yet, a number of controversial issues related to OEC biology and transplantation must be addressed to understand the rationale and expectations for OEC cell therapy approaches in SCI. This review provides information on these issues for spinal cord medicine clinicians.
Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs)
Glia, 2018
The prospects of achieving regeneration in the central nervous system (CNS) have changed, as most recent findings indicate that several species, including humans, can produce neurons in adulthood. Studies targeting this property may be considered as potential therapeutic strategies to respond to injury or the effects of demyelinating diseases in the CNS. While CNS trauma may interrupt the axonal tracts that connect neurons with their targets, some neurons remain alive, as seen in optic nerve and spinal cord (SC) injuries (SCIs). The devastating consequences of SCIs are due to the immediate and significant disruption of the ascending and descending spinal pathways, which result in varying degrees of motor and sensory impairment. Recent therapeutic studies for SCI have focused on cell transplantation in animal models, using cells capable of inducing axon regeneration like Schwann cells (SchCs), astrocytes, genetically modified fibroblasts and olfactory ensheathing glia cells (OECs). N...
Olfactory ensheathing glia and Schwann cells: two of a kind?
Cell and Tissue Research, 2002
Schwann cells have been shown to promote axonal regrowth and remyelination in the central (CNS) and peripheral nervous systems under experimental conditions. During development, OECs and Schwann cells emerge from the olfactory placode and the neural crest, respectively, thus sharing a common "peripheral" origin. Both cell types are known to express a number of different molecular markers in common, to display a similar morphological phenotype in culture and to respond to the same growth-promoting molecules. Contrary to Schwann cells, OECs are found in association with neuronal processes in the CNS constituting the olfactory nerve layer of the olfactory bulb. OECs maintain their growth-promoting capacity in the CNS during adult life supporting the lifelong axonal growth of olfactory receptor neurons. Thus, OECs are considered an intermediate cell type combining a "central" location with "peripheral" permissiveness. Recently, the regenerative potential of OECs has been demonstrated in a variety of studies. However, OECs are still less clearly defined than Schwann cells. On designing future therapeutical strategies for nerve injury and disease, the important question arises as to whether OECs and Schwann cells are comparable cell types or whether they, indeed, mediate specific effects, making either the one or the other suitable for special applications. The present review summarizes recent data on the in vitro and in vivo properties of OECs and critically compares the analogies and differences in the biology of both cell types relevant in the above-mentioned context.
Neurotrophic properties of olfactory ensheathing glia
Experimental Neurology, 2003
Olfactory ensheathing cells (OEC) constitute a specialized population of glia that accompany primary olfactory axons and have been reported to facilitate axonal regeneration after spinal cord injury in vivo. In the present report we describe OEC neurotrophic factor expression and neurotrophic properties of OECs in vitro. Investigation of the rat olfactory system during development and adulthood by radioactive in situ hybridization revealed positive labeling in the olfactory nerve layer for the neurotrophic molecules S-100beta, CNTF, BMP-7/OP-1, and artemin, as well as for the neurotrophic factor receptors RET and TrkC. Ribonuclease protection assay of cultured OEC revealed expression of NGF, BDNF, GDNF, and CNTF mRNA, while NT3 and NT4 mRNA were not detectable. In vitro bioassays of neurotrophic activity involved coculturing of adult OEC with embryonic chick ganglia and demonstrated increased neurite outgrowth from sympathetic, ciliary, and Remak's ganglia. However, when culturing the ganglia with OEC-conditioned medium, neurite outgrowth was not stimulated to any detectable extent. Our results suggest that the neurotrophic properties of OEC may involve secretion of neurotrophic molecules but that cellular interactions are crucial.
Clinical application of adult olfactory bulb ensheathing glia for nervous system repair
Experimental Neurology, 2011
The ability of adult olfactory bulb ensheathing glia (OB-OEG) to promote histological and functional neural repair has been broadly documented. Pre-clinical studies show that beneficial effects of adult OB-OEG are repeatable in the same type of spinal cord injury initially tested, in other spinal cord and CNS injury models, in different species and after the administration of these cells in different forms (either alone or in combination with other cells, drugs, products or devices). These studies demonstrate the reproducibility, robustness, fundamental nature and relevance of the findings. Therefore, the use of adult OB-OEG for spinal cord injury repair meets the scientific criteria established by the International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) for the translation to human application. Because there is so much heterogeneity in the way adult OEG is administered, each of these different OEG-based therapies must be individually categorized to determine whether they fulfill the requisites dictated by the consolidated regulatory body to be considered or not as a medicine. In the case they do, in Europe, they shall be subjected to the Regulatory European Framework for Advanced Therapy Medicinal Products and the European Clinical Trials Directive (Directives 2001/20/EC and 2009/120/EC). After a deep analysis of the European Regulation we have concluded that grafts consisting of suspensions of purified adult OEG, to be used for the promotion of axonal regeneration in the CNS, do not comply with the definition of Medicinal Product provided by the European Medicines Agency. In contrast, experimental therapies using OEG in combination with other cell types, drugs, products or devices, or genetically-modified OEG fall under the definitions of Medicinal Product. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.
Molecular Therapy, 2006
Immortalized cell lines of olfactory ensheathing glia (OEG) that maintain the proregenerative properties of primary cultures provide an unlimited source of OEG for both basic and applied studies. Indeed, one specific immortalized rat OEG clonal line (TEG3) proved to be as good as primary OEG in promoting neuritogenesis and axon regeneration in culture models. Thus, we examined the capacity of TEG3 to promote axonal repair in an animal model of spinal cord injury, dorsal column crush. TEG3 cells can acquire astrocyte-like or Schwann cell-like morphology depending on the conditions under which they are cultured. In the injured spinal cord, prelabeled TEG3 survived for at least 10 weeks after grafting and they integrated into the spinal cord, adopting Schwann cell-like, astrocyte-like, or intermediate morphologies. In TEG3-transplanted animals, sensory projection axons grow into the lesion site and there was robust sprouting/axonal growth of the corticospinal tract, both into and beyond the lesion site, after crushing of the spinal cord-dorsal columns. TEG3-transplanted animals also recovered sensory and motor function in tape removal and beam walking behavioral tests. These data indicate that certain immortalized cell lines derived from a single cell can maintain the regenerative properties of primary OEG.