Lipopolysaccharide induces human olfactory ensheathing glial apoptosis by promoting mitochondrial dysfunction and activating the JNK-Bnip3-Bax pathway.
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ABSTRACT:
SUBMITTER: He M
PROVIDER: S-EPMC6363633 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The in situ immunocytochemical properties of olfactory ensheathing cells (OECs) have been well studied in several small to medium sized animal models including rats, mice, guinea pigs, cats and canines. However, we know very little about the antigenic characteristics of OECs in situ within the adult and developing human olfactory bulb and nerve roots. To address this gap in knowledge we undertook an immunocytochemical analysis of the 11-19 pcw human foetal olfactory system. Human foetal OECs in situ possessed important differences compared to rodents in the expression of key surface markers. P75NTR was not observed in OECs but was strongly expressed by human foetal Schwann cells and perineurial olfactory nerve fibroblasts surrounding OECs. We define OECs throughout the 11-19 pcw human olfactory system as S100/vimentin/SOX10+ with low expression of GFAP. Our results suggest that P75NTR is a robust marker that could be utilised with cell sorting techniques to generate enriched OEC cultures by first removing P75NTR expressing Schwann cells and fibroblasts, and subsequently to isolate OECs after P75NTR upregulation in vitro. O4 and PSA-NCAM were not found to be suitable surface antigens for OEC purification owing to their ambiguous and heterogeneous expression. Our results highlight the importance of corroborating cell markers when translating cell therapies from animal models to the clinic.
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Project description:Bnip3 is a pro-apoptotic member of the Bcl-2 family that is down-regulated in pancreatic cancers, which correlates with resistance to chemotherapy and a worsened prognosis. In contrast, Bnip3 is up-regulated in heart failure and contributes to loss of myocardial cells during I/R (ischaemia/reperfusion). Bnip3 exerts its action at the mitochondria, but the mechanism by which Bnip3 mediates mitochondrial dysfunction is not clear. In the present study, we have identified Bax and Bak as downstream effectors of Bnip3-mediated mitochondrial dysfunction. Bnip3 plays a role in hypoxia-mediated cell death, but MEFs (mouse embryonic fibroblasts) derived from mice deficient in Bax and Bak were completely resistant to hypoxia even with substantial up-regulation of Bnip3. These cells were also resistant to Bnip3 overexpression, but re-expression of Bax or Bak restored susceptibility to Bnip3, suggesting that Bnip3 can act via either Bax or Bak. In contrast, Bnip3 overexpression in wild-type MEFs induced mitochondrial dysfunction with loss of membrane potential and release of cytochrome c. Cell death by Bnip3 was reduced in the presence of mPTP (mitochondrial permeability transition pore) inhibitors, but did not prevent Bnip3-mediated activation of Bax or Bak. Moreover, overexpression of Bnip3DeltaTM, a dominant-negative form of Bnip3, reduced translocation of GFP (green fluorescent protein)-Bax to mitochondria during sI/R (simulated I/R) in HL-1 myocytes. Similarly, down-regulation of Bnip3 using RNA interference decreased activation of Bax in response to sI/R in HL-1 myocytes. These results suggest that Bnip3 mediates mitochondrial dysfunction through activation of Bax or Bak which is independent of mPTP opening.
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Project description:The gradual deterioration following central nervous system (CNS) injuries or neurodegenerative disorders is usually accompanied by infiltration of degenerated and apoptotic neural tissue debris. A rapid and efficient clearance of these deteriorated cell products is of pivotal importance in creating a permissive environment for regeneration of those damaged neurons. Our recent report revealed that the phagocytic activity of olfactory ensheathing cells (OECs) can make a substantial contribution to neuronal growth in such a hostile environment. However, little is known about how to further increase the ability of OECs in phagocytosing deleterious products. Here, we used an in vitro model of primary cells to investigate the effects of lipopolysaccharide (LPS) and curcumin (CCM) co-stimulation on phagocytic activity of OECs and the possible underlying mechanisms. Our results showed that co-stimulation using LPS and CCM can significantly enhance the activation of OECs, displaying a remarkable up-regulation in chemokine (C-X-C motif) ligand 1, chemokine (C-X-C motif) ligand 2, tumor necrosis factor-α, and Toll-like receptor 4, increased OEC proliferative activity, and improved phagocytic capacity compared with normal and LPS- or CCM-treated OECs. More importantly, this potentiated phagocytosis activity greatly facilitated neuronal growth under hostile culture conditions. Moreover, the up-regulation of transglutaminase-2 and phosphatidylserine receptor in OECs activated by LPS and CCM co-stimulation are likely responsible for mechanisms underlying the observed cellular events, because cystamine (a specific inhibitor of transglutaminase-2) and neutrophil elastase (a cleavage enzyme of phosphatidylserine receptor) can effectively abrogate all the positive effects of OECs, including phagocytic capacity and promotive effects on neuronal growth. This study provides an alternative strategy for the repair of traumatic nerve injury and neurologic diseases with the application of OECs in combination with LPS and CCM.
| S-EPMC5398976 | biostudies-literature
Project description:Olfactory ensheathing glia (OEG) are distinct from other glia in their developmental origin, presence in both the peripheral and central nervous systems, and highly restricted location. OEG are present only in the olfactory lamina propria, olfactory nerve, and the outer two layers of the olfactory bulb, where they envelop bundles of olfactory sensory neuron axons in a manner distinct from myelination. Because of their unique properties and their association with the continually generated olfactory sensory neurons, OEG have attracted interest for their potential capacity to support axonal regeneration, for example, after spinal cord injury. However, study of the properties and function of OEG has been hampered by a paucity of neurochemical markers with which to identify and distinguish them definitively from other types of glia. Here we provide evidence through anatomical colocalization studies that OEG express the water channel aquaporin 1 (AQP1), both in vivo and in vitro. We propose that AQP1 expression represents an important distinguishing characteristic of OEG, which may impart unique function to these glia.
| S-EPMC2949966 | biostudies-literature
Project description:Olfactory ensheathing cells (OECs) are a unique class of glial cells with exceptional translational potential because of their ability to support axon regeneration in the central nervous system. Although OECs are similar in many ways to immature and nonmyelinating Schwann cells, and can myelinate large-diameter axons indistinguishably from myelination by Schwann cells, current dogma holds that OECs arise from the olfactory epithelium. Here, using fate-mapping techniques in chicken embryos and genetic lineage tracing in mice, we show that OECs in fact originate from the neural crest and hence share a common developmental heritage with Schwann cells. This explains the similarities between OECs and Schwann cells and overturns the existing dogma on the developmental origin of OECs. Because neural crest stem cells persist in adult tissue, including skin and hair follicles, our results also raise the possibility that patient-derived neural crest stem cells could in the future provide an abundant and accessible source of autologous OECs for cell transplantation therapy for the injured central nervous system.
| S-EPMC3000254 | biostudies-other
Project description:Olfactory ensheathing cells are thought to support regeneration and remyelination of damaged axons when transplanted into spinal cord injuries. Following transplantation, improved locomotion has been detected in many laboratory models and in dogs with naturally-occurring spinal cord injury; safety trials in humans have also been completed. For widespread clinical implementation, it will be necessary to derive large numbers of these cells from an accessible and, preferably, autologous, source making olfactory mucosa a good candidate. Here, we compared the yield of olfactory ensheathing cells from the olfactory mucosa using 3 different techniques: rhinotomy, frontal sinus keyhole approach and rhinoscopy. From canine clinical cases with spinal cord injury, 27 biopsies were obtained by rhinotomy, 7 by a keyhole approach and 1 with rhinoscopy. Biopsy via rhinoscopy was also tested in 13 cadavers and 7 living normal dogs. After 21 days of cell culture, the proportions and populations of p75-positive (presumed to be olfactory ensheathing) cells obtained by the keyhole approach and rhinoscopy were similar (~4.5 x 106 p75-positive cells; ~70% of the total cell population), but fewer were obtained by frontal sinus rhinotomy. Cerebrospinal fluid rhinorrhea was observed in one dog and emphysema in 3 dogs following rhinotomy. Blepharitis occurred in one dog after the keyhole approach. All three biopsy methods appear to be safe for harvesting a suitable number of olfactory ensheathing cells from the olfactory mucosa for transplantation within the spinal cord but each technique has specific advantages and drawbacks.
| S-EPMC6402693 | biostudies-literature
Project description:BackgroundZika virus (ZIKV) is an emerging arbovirus of the genus flavivirus that is associated with congenital Zika syndrome (CZS) in newborns. A wide range of clinical symptoms including intellectual disability, speech delay, coordination or movement problems, and hearing and vision loss, have been well documented in children with CZS. However, whether ZIKV can invade the olfactory system and lead to post-viral olfactory dysfunction (PVOD) remains unknown.MethodsWe investigated the susceptibility and biological responses of the olfactory system to ZIKV infection using mouse models and human olfactory organoids derived from patient olfactory mucosa.FindingsWe demonstrate that neonatal mice infected with ZIKV suffer from transient olfactory dysfunction when they reach to puberty. Moreover, ZIKV mainly targets olfactory ensheathing cells (OECs) and exhibits broad cellular tropism colocalizing with small populations of mature/immature olfactory sensory neurons (mOSNs/iOSNs), sustentacular cells and horizontal basal cells in the olfactory mucosa (OM) of immunodeficient AG6 mice. ZIKV infection induces strong antiviral immune responses in both the olfactory mucosa and olfactory bulb tissues, resulting in the upregulation of proinflammatory cytokines/chemokines and genes related to the antiviral response. Histopathology and transcriptomic analysis showed typical tissue damage in the olfactory system. Finally, by using an air-liquid culture system, we showed that ZIKV mainly targets sustentacular cells and OECs and support robust ZIKV replication.InterpretationOur results demonstrate that olfactory system represents as significant target for ZIKV infection, and that PVOD may be neglected in CZS patients.FundingStated in the acknowledgment.
| S-EPMC9931927 | biostudies-literature
Project description:We and others previously showed that in mouse embryos lacking the transcription factor Sox10, olfactory ensheathing cell (OEC) differentiation is disrupted, resulting in defective olfactory axon targeting and fewer gonadotropin-releasing hormone (GnRH) neurons entering the embryonic forebrain. The underlying mechanisms are unclear. Here, we report that OECs in the olfactory nerve layer express Frzb-encoding a secreted Wnt inhibitor with roles in axon targeting and basement membrane breakdown-from embryonic day (E)12.5, when GnRH neurons first enter the forebrain, until E16.5, the latest stage examined. The highest levels of Frzb expression are seen in OECs in the inner olfactory nerve layer, abutting the embryonic olfactory bulb. We find that Sox10 is required for Frzb expression in OECs, suggesting that loss of Frzb could explain the olfactory axon targeting and/or GnRH neuron migration defects seen in Sox10-null mice. At E16.5, Frzb-null embryos show significant reductions in both the volume of the olfactory nerve layer expressing the maturation marker Omp and the number of Omp-positive olfactory receptor neurons in the olfactory epithelium. As Omp upregulation correlates with synapse formation, this suggests that Frzb deletion indeed disrupts olfactory axon targeting. In contrast, GnRH neuron entry into the forebrain is not significantly affected. Hence, loss of Frzb may contribute to the olfactory axon targeting phenotype, but not the GnRH neuron phenotype, of Sox10-null mice. Overall, our results suggest that Frzb secreted from OECs in the olfactory nerve layer is important for olfactory axon targeting.
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Project description:Olfactory ensheathing cells (OECs) have been repeatedly implicated in mediating plasticity, particularly in situ in the olfactory nerve in which they support the extension of olfactory sensory neuron (OSN) axons from the olfactory epithelium to the olfactory bulb (OB). OECs are specialized glia whose processes surround OSN axon fascicles within the olfactory nerve and across the OB surface. Despite their purported importance in promoting axon extension, and following transplants, little is known about either morphology or biophysical properties of OECs in situ. In particular, cell-cell interactions that may influence OEC function are largely unexplored. Here, we studied OEC connectivity and morphology in slice preparations, preserving tissue structure and cell-cell interactions. Our analyses showed that OECs form a matrix of cellular projections surrounding axons, unique among glia, and express high levels of connexin-43. Lucifer Yellow injections revealed selective dye coupling among small subgroups of OECs. Two types of OECs were biophysically distinguished with whole-cell voltage-clamp recordings: (1) with low-input resistance (R(i)), linear current profiles, and frequently dye coupled; and (2) with high R(i), nonlinear current profiles, and infrequent dye coupling. Pharmacological blockade of gap junctions changed OEC membrane properties such that linear OECs became nonlinear. Double recordings indicated that the appearance of the nonlinear current profile was associated with the loss of electrical coupling between OECs. We conclude that the diversity of OEC current profiles can be explained by differences in gap-junction connectivity and discuss implications of this diversity for OEC influences on axon growth and excitability.
| S-EPMC2830329 | biostudies-literature
Project description: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.
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