Olfaction in Lamprey Pallium Revisited-Dual Projections of Mitral and Tufted Cells.

The presence of two separate afferent channels from the olfactory glomeruli to different targets in the brain is unravelled in the lamprey. The mitral-like cells send axonal projections directly to the piriform cortex in the ventral part of pallium, whereas the smaller tufted-like cells project separately and exclusively to a relay nucleus called the dorsomedial telencephalic nucleus (dmtn). This nucleus, located at the interface between the olfactory bulb and pallium, in turn projects to a circumscribed area in the anteromedial, ventral part of pallium. The tufted-like cells are activated with short latency from the olfactory nerve and terminate with mossy fibers on the dmtn cells, wherein they elicit large unitary excitatory postsynaptic potentials (EPSPs). In all synapses along this tufted-like cell pathway, there is no concurrent inhibition, in contrast to the mitral-like cell pathway. This is similar to recent findings in rodents establishing two separate exclusive projection patterns, suggesting an evolutionarily conserved organization.

Convergence of Olfactory Inputs within the Central Nervous System of a Cartilaginous and a Bony Fish: An Anatomical Indicator of Olfactory Sensitivity.

The volume of the olfactory bulbs (OBs) relative to the brain has been used previously as a proxy for olfactory capabilities in many vertebrate taxa, including fishes. Although this gross approach has predictive power, a more accurate assessment of the number of afferent olfactory inputs and the convergence of this information at the level of the telencephalon is critical to our understanding of the role of olfaction in the behaviour of fishes. In this study, we used transmission electron microscopy to assess the number of first-order axons within the olfactory nerve (ON) and the number of second-order axons in the olfactory peduncle (OP) in established model species within cartilaginous (brownbanded bamboo shark, Chiloscyllium punctatum [CP]) and bony (common goldfish, Carassius auratus [CA]) fishes. The total number of axons varied from a mean of 18.12 ± 7.50 million in the ON to a mean of 0.38 ± 0.21 million in the OP of CP, versus 0.48 ± 0.16 million in the ON and 0.09 ± 0.02 million in the OP of CA. This resulted in a convergence ratio of approximately 50:1 and 5:1, respectively, for these two species. Based on astroglial ensheathing, axon type (unmyelinated [UM] and myelinated [M]) and axon size, we found no differentiated tracts in the OP of CP, whereas a lateral and a medial tract (both of which could be subdivided into two bundles or areas) were identified for CA, as previously described. Linear regression analyses revealed significant differences not only in axon density between species and locations (nerves and peduncles), but also in axon type and axon diameter (p < 0.05). However, UM axon diameter was larger in the OPs than in the nerve in both species (p = 0.005), with no significant differences in UM axon diameter in the ON (p = 0.06) between species. This study provides an in-depth analysis of the neuroanatomical organisation of the ascending olfactory pathway in two fish taxa and a quantitative anatomical comparison of the summation of olfactory information. Our results support the assertion that relative OB volume is a good indicator of the level of olfactory input and thereby a proxy for olfactory capabilities.

Macrophage migration inhibitory factor and its binding partner HTRA1 are expressed by olfactory ensheathing cells.

Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity with key roles in neural regeneration and responses to pathogens, amongst a multitude of other functions. The expression of MIF and its binding partners has been characterised throughout the nervous system, with one key exception: the primary olfactory nervous system. Here, we showed in young mice (postnatal day 10) that MIF is expressed in the olfactory nerve by olfactory ensheathing glial cells (OECs) and by olfactory nerve fibroblasts. We also examined the expression of potential binding partners for MIF, and found that the serine protease HTRA1, known to be inhibited by MIF, was also expressed at high levels by OECs and olfactory fibroblasts in vivo and in vitro. We also demonstrated that MIF mediated segregation between OECs and J774a.1 cells (a monocyte/macrophage cell line) in co-culture, which suggests that MIF contributes to the fact that macrophages are largely absent from olfactory nerve fascicles. Phagocytosis assays of axonal debris demonstrated that MIF strongly stimulates phagocytosis by OECs, which indicates that MIF may play a role in the response of OECs to the continual turnover of olfactory axons that occurs throughout life.

Survival and Integration of Transplanted Olfactory Ensheathing Cells are Crucial for Spinal Cord Injury Repair: Insights from the Last 10 Years of Animal Model Studies.

Olfactory ensheathing cells (OECs), the glial cells of the primary olfactory nervous system, support the natural regeneration of the olfactory nerve that occurs throughout life. OECs thus exhibit unique properties supporting neuronal survival and growth. Transplantation of OECs is emerging as a promising treatment for spinal cord injury; however, outcomes in both animals and humans are variable and the method needs improvement and standardization. A major reason for the discrepancy in functional outcomes is the variability in survival and integration of the transplanted cells, key factors for successful spinal cord regeneration. Here, we review the outcomes of OEC transplantation in rodent models over the last 10 years, with a focus on survival and integration of the transplanted cells. We identify the key factors influencing OEC survival: injury type, source of transplanted cells, co-transplantation with other cell types, number and concentration of cells, method of delivery, and time of transplantation after the injury. We found that two key issues are hampering optimization and standardization of OEC transplantation: lack of (1) reliable methods for identifying transplanted cells, and (2) three-dimensional systems for OEC delivery. To develop OEC transplantation as a successful and standardized therapy for spinal cord injury, we must address these issues and increase our understanding of the complex parameters influencing OEC survival.

Strength in diversity: functional diversity among olfactory neurons of the same type.

Most animals depend upon olfaction to find food, mates, and to avoid predators. An animal's olfactory circuit helps it sense its olfactory environment and generate critical behavioral responses. The general architecture of the olfactory circuit, which is conserved across species, is made up of a few different neuronal types including first-order receptor neurons, second- and third-order neurons, and local interneurons. Each neuronal type differs in their morphology, physiology, and neurochemistry. However, several recent studies have suggested that there is intrinsic diversity even among neurons of the same type and that this diversity is important for neural function. In this review, we first examine instances of intrinsic diversity observed among individual types of olfactory neurons. Next, we review potential genetic and experience-based plasticity mechanisms that underlie this diversity. Finally, we consider the implications of intrinsic neuronal diversity for circuit function. Overall, we hope to highlight the importance of intrinsic diversity as a previously underestimated property of circuit function.

Semaphorin 3A as an inhibitive factor for migration of olfactory ensheathing cells through cofilin activation is involved in formation of olfactory nerve layer.

Olfactory ensheathing cells (OECs) migrate from olfactory epithelium towards olfactory bulb (OB), contributing to formation of the presumptive olfactory nerve layer during development. However, it remains unclear that molecular mechanism of regulation of OEC migration in OB. In the present study, we found that OECs highly expressed the receptors of semaphorin 3A (Sema3A) in vitro and in vivo, whereas Sema3A displayed a gradient expression pattern with higher in inner layer of OB and lower in outer layer of OB. Furthermore, the collapse assays, Boyden chamber migration assays and single-cell migration assays showed that Sema3A induced the collapse of leading front of OECs and inhibited OEC migration. Thirdly, the leading front of OECs exhibited adaptation in a protein synthesis-independent manner, and endocytosis-dependent manner during Sema3A-induced OEC migration. Finally, Sema3A-induced collapse of leading front was required the decrease of focal adhesion and a retrograde F-actin flow in a cofilin activation-dependent manner. Taken together, these results demonstrate that Sema3A as an inhibitive migratory factor for OEC migration through cofilin activation is involved in the formation of olfactory nerve layer.

Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of ß-amyloid oligomer.

Olfactory dysfunction is a common symptom associated with neurodegenerative diseases including Alzheimer's disease (AD). Although evidence exists to suggest that peripheral olfactory organs are involved in the olfactory dysfunction that accompanies AD pathology, the underlying mechanisms are not fully understood. As confirmed using behavioral tests, transgenic mice overexpressing a Swedish mutant form of human amyloid precursor proteins exhibited olfactory impairments prior to evidence of cognitive impairment. By measuring the expression of tyrosine hydroxylase, we observed that specific regions of the olfactory bulb (OB) in Tg2576 mice, specifically the ventral portion exhibited significant decreases in the number of dopaminergic neurons in the periglomerular regions from the early stage of AD. To confirm the direct linkage between these olfactory impairments and AD-related pathology, ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)-the initiating enzyme in Aß genesis-and ß-amyloid peptide (Aß), hallmarks of AD were analyzed. We found that an increase in BACE1 expression coincided with an elevation of amyloid-ß (Aß) oligomers in the ventral region of OB. Moreover, olfactory epithelium (OE), in particular the ectoturbinate in which axons of olfactory sensory neurons (OSNs) have direct connections with the dendrites of mitral/tufted cells in the ventral part of OB, exhibited significant decreases in both thickness and cell number even at early stages. This result suggests that Aß oligomer toxicity in the OE may have induced a decline in the number of OSNs and functional impairment of the olfactory system. We first demonstrated that disproportionate levels of regional damage in the peripheral olfactory system may be a specific symptom of AD with Aß oligomer accumulation occurring prior to damage within the CNS. This regional damage in the olfactory system early in the progression of AD may be closely related to AD-related pathological abnormality and olfactory dysfunction found in AD patients.

Contribution of the cyclic nucleotide gated channel subunit, CNG-3, to olfactory plasticity in Caenorhabditis elegans.

In Caenorhabditis elegans, the AWC neurons are thought to deploy a cGMP signaling cascade in the detection of and response to AWC sensed odors. Prolonged exposure to an AWC sensed odor in the absence of food leads to reversible decreases in the animal's attraction to that odor. This adaptation exhibits two stages referred to as short-term and long-term adaptation. Previously, the protein kinase G (PKG), EGL-4/PKG-1, was shown necessary for both stages of adaptation and phosphorylation of its target, the beta-type cyclic nucleotide gated (CNG) channel subunit, TAX-2, was implicated in the short term stage. Here we uncover a novel role for the CNG channel subunit, CNG-3, in short term adaptation. We demonstrate that CNG-3 is required in the AWC for adaptation to short (thirty minute) exposures of odor, and contains a candidate PKG phosphorylation site required to tune odor sensitivity. We also provide in vivo data suggesting that CNG-3 forms a complex with both TAX-2 and TAX-4 CNG channel subunits in AWC. Finally, we examine the physiology of different CNG channel subunit combinations.

The Glia Response after Peripheral Nerve Injury: A Comparison between Schwann Cells and Olfactory Ensheathing Cells and Their Uses for Neural Regenerative Therapies.

The peripheral nervous system (PNS) exhibits a much larger capacity for regeneration than the central nervous system (CNS). One reason for this difference is the difference in glial cell types between the two systems. PNS glia respond rapidly to nerve injury by clearing debris from the injury site, supplying essential growth factors and providing structural support; all of which enhances neuronal regeneration. Thus, transplantation of glial cells from the PNS is a very promising therapy for injuries to both the PNS and the CNS. There are two key types of PNS glia: olfactory ensheathing cells (OECs), which populate the olfactory nerve, and Schwann cells (SCs), which are present in the rest of the PNS. These two glial types share many similar morphological and functional characteristics but also exhibit key differences. The olfactory nerve is constantly turning over throughout life, which means OECs are continuously stimulating neural regeneration, whilst SCs only promote regeneration after direct injury to the PNS. This review presents a comparison between these two PNS systems in respect to normal physiology, developmental anatomy, glial functions and their responses to injury. A thorough understanding of the mechanisms and differences between the two systems is crucial for the development of future therapies using transplantation of peripheral glia to treat neural injuries and/or disease.

Transplantation of olfactory ensheathing cells promotes partial recovery in rats with experimental autoimmune encephalomyelitis.

OBJECTIVE: This study was to investigate the efficacy of olfactory ensheathing cell (OEC) transplantation on experimental autoimmune encephalomyelitis (EAE). METHODS: EAE models were established by guinea pig spinal cord homogenate (GPSCH) immunization in Lewis rats. OECs were purified and cultured from the olfactory nerve layer of SD rats, and then transplanted to the EAE models through the vena caudalis (Group A) or into the lateral cerebral ventricle (Group B). Neurological function scores and body weights were daily recorded following transplantation, and histological analysis was performed to assess the pathological changes in EAE rats. RESULTS: Cultured cells mainly exhibited bipolar or tripolar morphology, and the majority of these cells were positive for NGFR p75 staining. Neurological function scoring and the body weight measurement showed that, OEC transplantation could significantly improve the performance of EAE rats, and similar results were observed for the transplantation through the vena caudalis and into the lateral cerebral ventricle. Moreover, the transplanted OECs accumulated to the lesions in the brains of EAE rats, in spite of the different transplantation approaches. However, no significant differences in histopathology (HE and LFB staining) were observed between the OEC-transplanted groups and the control group. CONCLUSION: OEC transplantation could exert beneficial effects in the treatment of EAE, no matter which the cells were transplanted through the vena caudalis or into the lateral cerebral ventricle. Our findings might provide evidence for the clinical treatment of multiple sclerosis with cell transplantation.

Environmental CO2 inhibits Caenorhabditis elegans egg-laying by modulating olfactory neurons and evokes widespread changes in neural activity.

Carbon dioxide (CO2) gradients are ubiquitous and provide animals with information about their environment, such as the potential presence of prey or predators. The nematode Caenorhabditis elegans avoids elevated CO2, and previous work identified three neuron pairs called "BAG," "AFD," and "ASE" that respond to CO2 stimuli. Using in vivo Ca(2+) imaging and behavioral analysis, we show that C. elegans can detect CO2 independently of these sensory pathways. Many of the C. elegans sensory neurons we examined, including the AWC olfactory neurons, the ASJ and ASK gustatory neurons, and the ASH and ADL nociceptors, respond to a rise in CO2 with a rise in Ca(2+). In contrast, glial sheath cells harboring the sensory endings of C. elegans' major chemosensory neurons exhibit strong and sustained decreases in Ca(2+) in response to high CO2. Some of these CO2 responses appear to be cell intrinsic. Worms therefore may couple detection of CO2 to that of other cues at the earliest stages of sensory processing. We show that C. elegans persistently suppresses oviposition at high CO2. Hermaphrodite-specific neurons (HSNs), the executive neurons driving egg-laying, are tonically inhibited when CO2 is elevated. CO2 modulates the egg-laying system partly through the AWC olfactory neurons: High CO2 tonically activates AWC by a cGMP-dependent mechanism, and AWC output inhibits the HSNs. Our work shows that CO2 is a more complex sensory cue for C. elegans than previously thought, both in terms of behavior and neural circuitry.

Voltage-dependent K+ currents contribute to heterogeneity of olfactory ensheathing cells.

The olfactory nerve is permissive for axon growth throughout life. This has been attributed in part to the olfactory ensheathing glial cells that encompass the olfactory sensory neuron fascicles. Olfactory ensheathing cells (OECs) also promote axon growth in vitro and when transplanted in vivo to sites of injury. The mechanisms involved remain largely unidentified owing in part to the limited knowledge of the physiological properties of ensheathing cells. Glial cells rely for many functions on the properties of the potassium channels expressed; however, those expressed in ensheathing cells are unknown. Here we show that OECs express voltage-dependent potassium currents compatible with inward rectifier (Kir ) and delayed rectifier (KDR ) channels. Together with gap junction coupling, these contribute to the heterogeneity of membrane properties observed in OECs. The relevance of K(+) currents expressed by ensheathing cells is discussed in relation to plasticity of the olfactory nerve.

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons.

Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN axon extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and axon extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN axons have reached the OB. Over the next 6+ days the OSN axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN axon adhesion and lead us to propose a new model dividing axon extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN axons coalesce in glomeruli.

Differing phagocytic capacities of accessory and main olfactory ensheathing cells and the implication for olfactory glia transplantation therapies.

The rodent olfactory systems comprise the main olfactory system for the detection of odours and the accessory olfactory system which detects pheromones. In both systems, olfactory axon fascicles are ensheathed by olfactory glia, termed olfactory ensheathing cells (OECs), which are crucial for the growth and maintenance of the olfactory nerve. The growth-promoting and phagocytic characteristics of OECs make them potential candidates for neural repair therapies such as transplantation to repair the injured spinal cord. However, transplanting mixed populations of glia with unknown properties may lead to variations in outcomes for neural repair. As the phagocytic capacity of the accessory OECs has not yet been determined, we compared the phagocytic capacity of accessory and main OECs in vivo and in vitro. In normal healthy animals, the accessory OECs accumulated considerably less axon debris than main OECs in vivo. Analysis of freshly dissected OECs showed that accessory OECs contained 20% less fluorescent axon debris than main OECs. However, when assayed in vitro with exogenous axon debris added to the culture, the accessory OECs phagocytosed almost 20% more debris than main OECs. After surgical removal of one olfactory bulb which induced the degradation of main and accessory olfactory sensory axons, the accessory OECs responded by phagocytosing the axon debris. We conclude that while accessory OECs have the capacity to phagocytose axon debris, there are distinct differences in their phagocytic capacity compared to main OECs. These distinct differences may be of importance when preparing OECs for neural transplant repair therapies.

Primer caso descrito de parálisis aislada, completa y fluctuante del III nervio craneal como forma de inicio de un mieloma múltiple / First case described of isolated, complete and fluctuating cranial nerve III palsy heralding multiple myeloma

Introducción. El mieloma múltiple es la neoplasia de células plasmáticas más frecuente. Al ser incurable, el tratamiento persigue obtener el mayor tiempo de supervivencia libre de clínica. Constituye una causa extremadamente rara de afectación de los nervios craneales y es producido habitualmente por un plasmocitoma intracraneal. Presentamos un caso de mieloma múltiple, que asociaba un plasmocitoma intracraneal y que comenzó clínicamente con parálisis aislada, completa y fluctuante del III nervio craneal. Caso clínico. Mujer de 63 años que acudió a urgencias por presentar un cuadro clínico oscilante, consistente en diplopía binocular horizontal y, posteriormente, cefalea. La exploración neurooftalmológica reveló una parálisis completa del III nervio craneal derecho. Se solicitó una tomografía axial computarizada craneal urgente, que reveló múltiples lesiones osteolíticas diploicas, asociando una de ellas componente de partes blandas en la hendidura esfenoidal derecha. La paciente fue ingresada, y se le diagnosticó posteriormente un mieloma múltiple IgA-k. Tras recibir inducción quimioterápica y ser sometida a un trasplante autólogo de progenitores hematopoyéticos, alcanzó la remisión completa. Conclusiones. El mieloma múltiple es un trastorno raro de los nervios craneales, una causa muy infrecuente de parálisis aislada y completa del III nervio craneal y menos aún fluctuante, y no se ha encontrado ningún caso publicado con este inicio clínico. Tener en cuenta las posibles manifestaciones neurooftalmológicas del mieloma múltiple puede contribuir a un diagnóstico precoz y a una incidencia positiva sobre el curso de esta enfermedad (AU)

Introduction. Multiple myeloma is the most common plasma-cell malignancy. To be incurable, treatment aims to obtain the longest non-clinical survival time. Cranial nerve palsy in multiple myeloma is extremely rare and is usually due to an intracranial plasmacytoma. We present a multiple myeloma case, with an intracranial plasmacytoma, which debuted clinically with isolated, complete and fluctuating cranial nerve III palsy. Case report. A 63-year-old woman presented an oscillating clinical picture, consisting of horizontal binocular diplopia and later, headache. The neuro-ophthalmologic examination revealed a complete cranial nerve III palsy of the right eye. An urgent cranial CT-scan was requested. It showed multiple diploic osteolytic lesions, associating soft-parts component in the right superior orbital fissure. The patient was admitted, being diagnosed subsequently of IgA-k multiple myeloma. After receiving induction-chemotherapy and undergoing autologous stem cell transplantation, she achieved full remission. Conclusions. Multiple myeloma is a rare cranial nerves disorder, very uncommon cause of cranial nerve III full isolated paralysis and even less fluctuating, not having found any case published with this clinical onset. Awareness of possible multiple myeloma neuro-ophthalmic manifestations may bring about an early diagnosis and a positive impact on the disease course (AU)

Development of the terminal nerve system in the shark Scyliorhinus canicula.

The nervus terminalis (or terminal nerve) system was discovered in an elasmobranch species more than a century ago. Over the past century, it has also been recognized in other vertebrate groups, from agnathans to mammals. However, its origin, functions or relationship with the olfactory system are still under debate. Despite the abundant literature about the nervus terminalis system in adult elasmobranchs, its development has been overlooked. Studies in other vertebrates have reported newly differentiated neurons of the terminal nerve system migrating from the olfactory epithelium to the telencephalon as part of a 'migratory mass' of cells associated with the olfactory nerve. Whether the same occurs in developing elasmobranchs (adults showing anatomically separated nervus terminalis and olfactory systems) has not yet been determined. In this work we characterized for the first time the development of the terminal nerve and ganglia in an elasmobranch, the lesser spotted dogfish (Scyliorhinus canicula), by means of tract-tracing techniques combined with immunohistochemical markers for the terminal nerve (such as FMRF-amide peptide), for the developing components of the olfactory system (Gα0 protein, GFAP, Pax6), and markers for early postmitotic neurons (HuC/D) and migrating immature neurons (DCX). We discriminated between embryonic olfactory and terminal nerve systems and determined that both components may share a common origin in the migratory mass. We also localized the exact point where they split off near the olfactory nerve-olfactory bulb junction. The study of the development of the terminal nerve system in a basal gnathostome contributes to the knowledge of the ancestral features of this system in vertebrates, shedding light on its evolution and highlighting the importance of elasmobranchs for developmental and evolutionary studies.

Molecular clock regulates daily α1-2-fucosylation of the neural cell adhesion molecule (NCAM) within mouse secondary olfactory neurons.

The circadian clock regulates various behavioral and physiological rhythms in mammals. Circadian changes in olfactory functions such as neuronal firing in the olfactory bulb (OB) and olfactory sensitivity have recently been identified, although the underlying molecular mechanisms remain unknown. We analyzed the temporal profiles of glycan structures in the mouse OB using a high-density microarray that includes 96 lectins, because glycoconjugates play important roles in the nervous system such as neurite outgrowth and synaptogenesis. Sixteen lectin signals significantly fluctuated in the OB, and the intensity of all three that had high affinity for α1-2-fucose (α1-2Fuc) glycan in the microarray was higher during the nighttime. Histochemical analysis revealed that α1-2Fuc glycan is located in a diurnal manner in the lateral olfactory tract that comprises axon bundles of secondary olfactory neurons. The amount of α1-2Fuc glycan associated with the major target glycoprotein neural cell adhesion molecule (NCAM) varied in a diurnal fashion, although the mRNA and protein expression of Ncam1 did not. The mRNA and protein expression of Fut1, a α1-2-specific fucosyltransferase gene, was diurnal in the OB. Daily fluctuation of the α1-2Fuc glycan was obviously damped in homozygous Clock mutant mice with disrupted diurnal Fut1 expression, suggesting that the molecular clock governs rhythmic α1-2-fucosylation in secondary olfactory neurons. These findings suggest the possibility that the molecular clock is involved in the diurnal regulation of olfaction via α1-2-fucosylation in the olfactory system.

Understanding the neural repair-promoting properties of olfactory ensheathing cells.

Olfactory ensheathing glial cells (OECs) are a specialized type of glia that form a continuously aligned cellular pathway that actively supports unprecedented regeneration of primary olfactory axons from the periphery into the central nervous system. Implantation of OECs stimulates neural repair in experimental models of spinal cord, brain and peripheral nerve injury and delays disease progression in animal models for neurodegenerative diseases like amyotrophic lateral sclerosis. OECs implanted in the injured spinal cord display a plethora of pro-regenerative effects; they promote axonal regeneration, reorganize the glial scar, remyelinate axons, stimulate blood vessel formation, have phagocytic properties and modulate the immune response. Recently genome wide transcriptional profiling and proteomics analysis combined with classical or larger scale "medium-throughput" bioassays have provided novel insights into the molecular mechanism that endow OECs with their pro-regenerative properties. Here we review these studies and show that the gaps that existed in our understanding of the molecular basis of the reparative properties of OECs are narrowing. OECs express functionally connected sets of genes that can be linked to at least 10 distinct processes directly relevant to neural repair. The data indicate that OECs exhibit a range of synergistic cellular activities, including active and passive stimulation of axon regeneration (by secretion of growth factors, axon guidance molecules and basement membrane components) and critical aspects of tissue repair (by structural remodeling and support, modulation of the immune system, enhancement of neurotrophic and antigenic stimuli and by metabolizing toxic macromolecules). Future experimentation will have to further explore the newly acquired knowledge to enhance the therapeutic potential of OECs.

The potential therapeutic applications of olfactory ensheathing cells in regenerative medicine.

Olfactory ensheathing cells (OECs) are unique glia cells restricted to the primary olfactory system including the olfactory mucosa, olfactory nerve, and the outer nerve layer of the olfactory bulb. OECs guide growing olfactory axons from the neurons of the nasal cavity olfactory mucosa to the olfactory bulb to connect both the peripheral nervous system (PNS) and central nervous system (CNS). Based on these specialized abilities of OECs, transplantation of OECs to injury sites has been widely investigated for their potential therapeutic applications in neural repair in different injuries. In this article, we reviewed the properties of OECs and their roles in olfactory regeneration and in treatment of different injuries including spinal cord injury, PNS injury, and stroke and neurodegenerative diseases.

Transcription factor Runx1 inhibits proliferation and promotes developmental maturation in a selected population of inner olfactory nerve layer olfactory ensheathing cells.

The olfactory system undergoes persistent regeneration throughout life. Olfactory ensheathing cells (OECs) are a specialized class of glia found exclusively in the olfactory system. OECs wrap olfactory sensory neuron axons and support their growth from the olfactory epithelium, and targeting to the olfactory bulb, during development and life-long regeneration. Because of this function and their ability to cross the boundary between central and peripheral nervous systems, OECs are attractive candidates for cell-based regenerative therapies to promote axonal repair in the injured nervous system. OECs are a molecularly, topologically and functionally heterogeneous group of cells and the mechanisms underlying the development and function of specific OEC subpopulations are poorly defined. This situation has affected the outcome and interpretation of OEC-based regenerative strategies. Here we show that the transcription factor Runx1 is selectively expressed in OECs of the inner olfactory nerve layer of the mouse olfactory bulb and in their precursors in the OEC migratory mass. Furthermore, we provide evidence that in vivo knockdown of mouse Runx1 increases the proliferation of the OECs in which Runx1 is expressed. Conversely, Runx1 overexpression in primary cultures of OECs reduces cell proliferation in vitro. Decreased Runx1 activity also leads to an increase in Runx1-expressing OEC precursors, with a parallel decrease in the number of more developmentally mature OECs. These results identify Runx1 as a useful new marker of a distinct OEC subpopulation and suggest that Runx1 is important for the development of this group of OECs. These observations provide an avenue for further exploration into the molecular mechanisms underlying the development and function of specific OEC subpopulations.