Chitinase-Like Protein Ym2 (Chil4) Regulates Regeneration of the Olfactory Epithelium via Interaction with Inflammation (original) (raw)
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Accumulation of Ym1/2 protein in the mouse olfactory epithelium during regeneration and aging
Neuroscience, 2004
A unique feature of the olfactory system is its efficiency to produce new neurons in the adult. Thus, destruction of the olfactory receptor neurons (ORNs) using chemical (intranasal perfusion with ZnSO 4 ) or surgical (axotomy or bulbectomy) methods, leads to an enhanced rate of proliferation of their progenitors and to complete ORNs regeneration. The aim of our study was to identify new factors implied in this regenerative process. Using an electrophoretic method, we observed the accumulation of a 42 kDa protein after axotomy in the olfactory mucosa, but not in the olfactory bulb. Its expression started after a few days following injury and increased massively during the phase of ORN regeneration. The purification and the sequence characterization revealed that this protein was Ym1/2, recently identified in activated macrophages present in various tissues during inflammation. Western blotting analysis of Ym1/2 confirmed the accumulation of this protein in the regenerating olfactory mucosa consecutively to olfactory axotomy or bulbectomy but also after ZnSO 4 irrigation of the nasal cavity. In the olfactory mucosa of control mice, Ym1/2 was hardly detectable in young animals and became more and more abundant with increasing age. In injured and aged mice, Ym1/2 mainly accumulates in the cytoplasm of supporting cells as well as in other cells located throughout the olfactory epithelium. Our results suggest that Ym1/2 is involved in olfactory epithelium remodeling following several kinds of lesions of the adult olfactory mucosa and support the view of a critical role of inflammatory cues in neurodegeneration and aging.
Injury Activates Transient Olfactory Stem Cell States with Diverse Lineage Capacities
Cell stem cell, 2017
Tissue homeostasis and regeneration are mediated by programs of adult stem cell renewal and differentiation. However, the mechanisms that regulate stem cell fates under such widely varying conditions are not fully understood. Using single-cell techniques, we assessed the transcriptional changes associated with stem cell self-renewal and differentiation and followed the maturation of stem cell-derived clones using sparse lineage tracing in the regenerating mouse olfactory epithelium. Following injury, quiescent olfactory stem cells rapidly shift to activated, transient states unique to regeneration and tailored to meet the demands of injury-induced repair, including barrier formation and proliferation. Multiple cell fates, including renewed stem cells and committed differentiating progenitors, are specified during this early window of activation. We further show that Sox2 is essential for cells to transition from the activated to neuronal progenitor states. Our study highlights strat...
Journal of Neurochemistry, 2008
The persistence and ability of the olfactory system to regenerate its neuroepithelium throughout adulthood by replacing damaged or dead neurons is unique in the mammalian nervous system. Such replacement and proliferation are possible as a result of the presence of precursor, multipotent cells in the olfactory neuroepithelium (ON). These precursor cells possess the ability to differentiate into either mature olfactory receptor neurons (ORNs) or nonneuronal supporting cells (Huard et al. 1998). The regenerative capacity of the ON, its reconstitution after injury and the re-innervation of the olfactory bulb have been studied extensively (Gage 2000; Schwob 2002). There is increasing knowledge regarding olfactory stem cell regulation and the transcriptional changes that occur during regeneration of the ON (Beites et al. 2005; Shetty et al. 2005; Nicolay et al. 2006). However, questions still remain about the genetic and molecular events and local environmental trophic influences that control and up-regulate olfactory stem cell activity. In fact, the precise identity of the olfactory stem cell is still unknown. The structure of the ON is well defined and contains distinct proliferating cell populations that give rise to transit amplifying progenitors that can differentiate into ORNs (Beites et al. 2005). Previous studies have shown that horizontal basal cells (HBCs) that reside on the basal lamina are proliferative and are able to differentiate into neurons and supporting cells (Mackay-Sim and Kittel 1991; Carter et al. 2004; Comte et al. 2004; Leung et al. 2007). Retroviral studies in vivo show that following injury globose basal cells (GBCs) are able to give rise to ORNs as well as supporting cells (
Neural Regeneration Research, 2022
Olfactory ensheathing cells (OECs) from the olfactory bulb (OB) and the olfactory mucosa (OM) have the capacity to repair nerve injury. However, the difference in the therapeutic effect between OB-derived OECs and OM-derived OECs remains unclear. In this study, we extracted OECs from OB and OM and compared the gene and protein expression profiles of the cells using transcriptomics and non-quantitative proteomics techniques. The results revealed that both OB-derived OECs and OM-derived OECs highly expressed genes and proteins that regulate cell growth, proliferation, apoptosis and vascular endothelial cell regeneration. The differentially expressed genes and proteins of OB-derived OECs play a key role in regulation of nerve regeneration and axon regeneration and extension, transmission of nerve impulses and response to axon injury. The differentially expressed genes and proteins of OM-derived OECs mainly participate in the positive regulation of inflammatory response, defense response, cytokine binding, cell migration and wound healing. These findings suggest that differentially expressed genes and proteins may explain why OB-derived OECs and OM-derived OECs exhibit different therapeutic roles. This study was approved by the Animal Ethics Committee of the General Hospital of Ningxia Medical University (approval No. 2017-073) on February 13, 2017.
Identification and molecular regulation of neural stem cells in the olfactory epithelium
Experimental Cell Research, 2005
The sensory neurons that subserve olfaction, olfactory receptor neurons (ORNs), are regenerated throughout life, making the neuroepithelium in which they reside [the olfactory epithelium (OE)] an excellent model for studying how intrinsic and extrinsic factors regulate stem cell dynamics and neurogenesis during development and regeneration. Numerous studies indicate that transcription factors and signaling molecules together regulate generation of ORNs from stem and progenitor cells during development, and work on regenerative neurogenesis indicates that these same factors may operate at postnatal ages as well. This review describes our current knowledge of the identity of the OE neural stem cell; the different cell types that are thought to be the progeny (directly or indirectly) of this stem cell; and the factors that influence cell differentiation in the OE neuronal lineage. We review data suggesting that (1) the ORN lineage contains three distinct proliferating cell types-a stem cell and two populations of transit amplifying cells; (2) in established OE, these three cell types are present within the basal cell compartment of the epithelium; and (3) the stem cell that gives rise ultimately to ORNs may also generate two glial cell types of the primary olfactory pathway: sustentacular cells (SUS), which lie within OE proper; and olfactory ensheathing cells (OEC), which envelope the olfactory nerve. In addition, we describe factors that are both made by and found within the microenvironment of OE stem and progenitor cells, and which exert crucial growth regulatory effects on these cells. Thus, as with other regenerating tissues, the basis of regeneration in the OE appears be a population of stem cells, which resides within a microenvironment (niche) consisting of factors crucial for maintenance of its capacity for proliferation and differentiation.
Glia, 2011
Olfactory ensheathing cells (OECs) support the regeneration of olfactory sensory neurons throughout life, however it remains unclear how OECs respond to a major injury. We have examined the proliferation and migration of OECs following unilateral bulbectomy in postnatal mice. S100ß-DsRed and OMP-ZsGreen transgenic mice were used to visualise OECs and olfactory neurons, respectively, and we used the thymidine analogue ethynyl deoxyuridine (EdU) to identify cells that were proliferating at the time of administration. Following unilateral bulbectomy, there was an initial phase of OEC proliferation throughout the olfactory pathway with a peak of proliferation occurring 2-7 days after the injury. A second phase of proliferation also occurred in which precursors localised within the olfactory mucosa divided to replenish the OEC population. We then tracked the positions of OECs that had proliferated and found that there was a progressive increase in OECs in the cavity for at least 12-16 days after injury which could not be accounted for solely by local proliferation of OECs within the cavity. These results suggest that OECs migrated from the peripheral olfactory nerve to populate the mass of cells that filled cavity left by bulbectomy. Our results demonstrate that following injury to the olfactory nervous system, the OEC population is replenished by migration of cells that arise from both local proliferation of OECs throughout the olfactory nerve pathway as well as from precursor cells in the olfactory mucosa.
Trends in Stem Cell Biology and Technology, 2009
We investigated whether human cord blood-selected CD133 + stem cells (HSC) may engraft the olfactory mucosa and contribute to restoration of neuro-olfactory epithelium (NE) in nod-scid mice damaged by dichlobenil. The herbicide dichlobenil selectively causes necrosis of the dorsomedial part of the NE and underlying mucosa, while the lateral part of the olfactory region remains undamaged. The aim of this research was to demonstrate that HSC stimulate self-renewal of neuronal stem cells and promote their differentiation into bipolar olfactory neurons to replace the injured NE. By PCR, we tested the presence of three human-specific microsatellites (CODIS; Combined DNS Index System), used as DNA markers for traceability of the engrafted cells, demonstrating their presence in various tissues of the host, including the olfactory mucosa, 1 month after transplantation. By immunohistochemistry and lectin staining, we demonstrated that, in injured mice, HSC contributed to stimulating residual endogenous olfactory neurons, promoting recovery of the original phenotype of the NE, in contrast to the lack of spontaneous regeneration in similar injured areas always seen in the nontransplanted control mice. Multiple colour fluorescence in situ hybridisation (M-FISH) analysis detected seven human genomic sequences present in different chromosomes and provided further evidence of positive prolonged engraftment of chimeric cells in the olfactory mucosa. This study provides the first evidence that transplanted HSC migrating to the neuro-olfactory mucosa may contribute to NE structure restoration with resumption of the sensorineural olfactory loss.
The role of olfactory ensheating cells in regenerative medicine: review of the literature
Romanian Journal of Rhinology, 2015
Olfactory ensheathing cells (OECs) join olfactory axons in their entrance to the central nervous system, representing a unique population of glial cells with functions in olfactory neurogenesis, axonal growth and olfactory bulb formation. Olfactory ensheathing cells have a great potential to induce repair for neural injuries, in central nervous system and peripheral nervous system, existing numerous experimental and clinical studies lately, reporting beneficial effects in anatomical and functional recovery. Studies are also conducted in order to establish possible pro-regenerative effects of the OECs, their potential in tissue repair and ability to modulate the immune system. The aim of this paper was to review the properties of olfactory ensheathing cells and their potential therapeutic role in regenerative medicine.
In vitro Maintenance of Olfactory Mucosa: with Enriched Olfactory Ensheathing Cells
Journal of Stem Cell Research & Therapy, 2013
Human Olfactory Mucosa (OM) regulates olfaction through axonal regeneration and myelination mediated by stem cells and Olfactory Ensheathing Cells (OECs) resident in the niche. Purified OECs/olfactory biopsies have been utilized for functional recovery in different Spinal Cord Injury (SCI) models. However, recent reports find this debatable where we propose primary culture of OM, basal cells of olfactory epithelium and olfactory ecto-mesenchymal stem cells. Our defined culture conditions improve the life span of OM with enrichment of OECs providing a strategy for employment for SCI/cochlear damage repair. Briefly, OM post-collection, was non-enzymatically sliced, cultured for 6 weeks and cells characterized morphologically, immuno-cytochemically and western blotting. By day 21, ~70% GFAP and p75NTR stained, spindle shaped astrocyte-like and flattened sheet-like OECs displayed axonal remyelination. By day 30, caspase 3, 8, 9 (gene-product and activity), phospho-p53 negative; GFAP and p75NTR positive dense, overlapping mass of cells was found. This was accompanied with degenerative changes by 6 weeks through GFAP staining. Conversely, trypsination on day 21 resulted in >95% OECs with flattened morphology, GFAP and p75NTR positivity. The human derived OECs were compared with the 2-day SD rat Olfactory Bulb Cells cultured for 2 weeks in F12 media (GFAP and p75NTR positive). Hence, cultured olfactory mucosa displaying axonal regeneration with OECs in culture provides a vehicle for SCI/cochlear damage repair studies.
Morphological and functional plasticity of olfactory ensheathing cells
Journal of Neurocytology, 2005
In the primary olfactory pathway, olfactory ensheathing cells (OECs) extend processes to envelop bundles of olfactory axons as they course towards their termination in the olfactory bulb. The expression of growth-promoting adhesion and extracellular matrix molecules by OECs, and their spatially close association with olfactory axons are consistent with OECs being involved in promoting and guiding olfactory axon growth. Because of this, OECs have been employed as a possible tool for inducing axonal regeneration in the injured adult CNS, resulting in significant functional recovery in some animal models and promising outcomes from early clinical applications. However, fundamental aspects of OEC biology remain unclear. This brief review discusses some of the experimental data that have resulted in conflicting views with regard to the identity of OECs. We present here recent findings which support the notion of OECs as a single but malleable phenotype which demonstrate extensive morphological and functional plasticity depending on the environmental stimuli. The review includes a discussion of the normal functional role of OECs in the developing primary olfactory pathway as well as their interaction with regenerating axons and reactive astrocytes in the novel environment of the injured CNS. The use of OECs to induce repair in the injured nervous system reflects the functional plasticity of these cells. Finally, we will explore the possibility that recent microarray data could point to OECs assuming an innate immune function or playing a role in modulating neuroinflammation.