Academic literature on the topic 'Olfactory ensheathing cells'

Abstract 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.

Enriched cultures of olfactory ensheathing cells and neural stem/progenitor cells were obtained according to our developed protocols from the olfactory mucosa of rat and human. It has been shown that only transplantation of human and rat olfactory ensheathing cells leads to a significant decrease in the size of cysts, as well as their complete disappearance in some animals.

We report a rare case of olfactory ensheathing cell tumor. A female presented a large soft mass extending medially to the olfactory cleft and laterally to the middle meatus in the left nasal cavity. Imaging studies confirmed a cystic mass extending superiorly into the frontal lobe, indicating that the tumor arouse from the olfactory mucosa. A subtotal resection was achieved through an endoscopic endonasal approach without operative complications. Immunohistochemically constituent cells were diffusely positive for S-100 protein, but olfactory ensheathing cell tumor was diagnosed by negative staining for Leu7 (CD57). This case indicates that olfactory ensheathing cell tumor should be included in differential diagnoses for the olfactory cleft tumors.

A large body of work supports the proposal that transplantation of olfactory ensheathing cells (OECs) into nerve or spinal cord injuries can promote axonal regeneration and remyelination. Yet, some investigators have questioned whether the transplanted OECs associate with axons and form peripheral myelin, or if they recruit endogenous Schwann cells that form myelin. Olfactory bulbs from transgenic mice expressing the enhanced green fluorescent protein (eGFP) under the control of the 2-3-cyclic nucleotide 3-phosphodiesterase (CNPase) promoter were studied. CNPase is expressed in myelin-forming cells throughout their lineage. We examined CNPase expression in both in situ in the olfactory bulb andin vitroto determine if OECs express CNPase commensurate with their myelination potential. eGFP was observed in the outer nerve layer of the olfactory bulb. Dissociated OECs maintained in culture had both intense eGFP expression and CNPase immunostaining. Transplantation of OECs into transected peripheral nerve longitudinally associated with the regenerated axons. These data indicate that OECs in the outer nerve layer of the olfactory bulb of CNPase transgenic mice express CNPase. Thus, while OECs do not normally form myelin on olfactory nerve axons, their expression of CNPase is commensurate with their potential to form myelin when transplanted into injured peripheral nerve.

Currently, most cellular therapeutic effects for nervous diseases cannot be proven in a multicenter, randomized, double-blind placebo-control clinical trials, except for a few kinds of cells such as olfactory ensheathing cells. These cells show significant improvements in functional recovery and quality of life for patients with chronic ischemic stroke. Also, olfactory neuron transplantation has promising neurorestorative effects on patients with vascular dementia. Human olfactory neuroepithelium can spontaneously and sustainably regenerate or produce new olfactory neurons and glial cell types for decades or a lifetime. The neurorestorative mechanisms of olfactory ensheathing cells are well known; however, little is known about the neurorestorative mechanisms of olfactory neurons. Therefore, I hypothesize that the neurorestorative mechanisms of olfactory neurons after transplantation: (1) can well migrate where they are needed and become local functional neurons, as they need to compensate or replace; (2) must be regulated by some special molecular factors to elongate their axons, modulate or direct synapses to correctly recognize and connect the target cells, and integrate functions. Based on olfactory neuroepithelium cells displaying the special characterization, neurorestorative mechanisms, clinical therapeutic achievements, and hypotheses of effective mechanisms, they (olfactory ensheathing cells and olfactory neurons) may be the most efficient instruments of neurorestoration.

Transplantation of olfactory ensheathing cells (OEC) is one of the most promising current approaches to repair spinal cord injury. The encouraging results from transplantation of OECs in animal models have led to several clinical applications of these cells in spinal cord injury. The first controlled clinical trial was carried out by Mackay-Sim, Féron and colleagues (Mackay-Sim et al., 2008). A number of neurosurgical teams have also implanted foetal OECs (Huang et al., 2003) or minced whole mucosal tissue (Lima et al., 2006) into spinal injuries. So far the reported functional benefits are only moderate. The Mackay-Sim team reported no improvements while others reported minor improvements (including an ongoing trial by Pawel Tabakow’s team in Poland; personal communication). The basic conclusion is that OEC transplantation is feasible and safe. However, in the studies where suspensions of OECs were used there were not enough cells to fill the lesion, and no materials were used to bridge the gaps. In order to progress to more effective transplants the two areas addressed in this thesis will be important – what is the best source of adequate numbers of cells, and what biomaterials can be used to bridge the gaps. In addressing the twin necessities of (a) identifying the tissue source needed to provide sufficient cells for transplantation and (b) the problem of bridging the large gaps present in spinal cord injuries, the results of this study were directed towards two issues. (a) The questions of cell source and proliferation were addressed by establishing the quantitative baseline for the yield of primary cultures from the olfactory bulb, and the whole and split olfactory mucosa and characterising the heterogeneity of these cultures in search for any difference between bulbar and mucosal OECs. The study of flow cytometric simultaneous antigenic bivariate cell cycle of purified OECs and ONFs from these four sources revealed the evolution of population heterogeneity and its strikingly differences between these four sources of primary tissue with additional populations that were not previously described. An unexpected highly proliferative p75+ population in the stripped mucosal epithelium was also characterised. Correlation study of the cell proliferation and population evolution revealed cell autonomous among the difference sources. (b) The feasibility of a synthesis biomaterial for the deployment of OECs and olfactory nerve fibroblasts (ONFs) as a transplant was addressed by designing and developing an electrospun PLGA nanocomposite nanofibre construct with a myriad of microfabrication techniques, focusing on how OECs and ONFs can be deployed during tissue culture and transplantation. The techniques included nanocomposite electrospinning, replica moulding from photolithographed silicon mould, design of tissue-culture membrane insert, and laser ablation. The biocompatibility study showed that when grown on a fibre mesh structured at the nano-scale, OECs responded by adopting the elongated form comparable to that which occurs when the convey regenerating fibres cross small lesions in in vivo transplants. Preliminary functional studies of using the nanocomposite nanofibers as a neural scaffold in the organotypic entorhino-hippocampus slice co-culture data provide an indication that the nanofibres are compatible with tissue and allow migration of astrocytes and growth of nerve fibres. These observations will be important in future attempts to derive larger cell populations for transplantation. The anticipated use of the OEC nanofibre prosthesis would be in the application of autologous human OECs for bridging the gap in spinal cord lesions.

Olfactory ensheathing cells (OECs), the glia of the olfactory nerve, are promising candidates for patient-specific cell-mediated repair of both peripheral nerves and the spinal cord. The recent discovery that OECs originate from the neural crest, rather than the olfactory epithelium as previously thought, potentially means that homogeneous populations of OECs for repair could be expanded in culture from neural crest stem cells persisting in the patient's own skin and hair follicles. The first step towards this long-term goal is to understand the molecular mechanisms underlying neural crest differentiation into OECs, as opposed to Schwann cells (the glia of all other peripheral nerves), which are less effective in spinal cord repair. To identify transcription factors and signalling pathways that might be involved in OEC versus Schwann cell differentiation, I took an unbiased transcriptome profiling approach. Taking advantage of Sox10 expression throughout both OEC and Schwann cell development, I used laser-capture microdissection on cryosections of mouse embryos carrying a Sox10:H2BVenus transgene, to isolate OEC subpopulations (olfactory mucosal OECs, from the olfactory nerve, and olfactory nerve layer OECs, from the olfactory nerve layer surrounding the olfactory bulb) at different stages of development, and Schwann cells from trigeminal nerve branches on the same sections, for RNA-seq and cross-wise comparison of transcriptomes. Validation of candidate genes by in situ hybridisation revealed some contamination with adjacent cells from mesenchyme, olfactory epithelium or olfactory bulb, but also identified the expression in developing OECs of various genes previously reported to be expressed in adult OECs, and of over 20 genes previously unknown in OECs. Some of these genes are expressed by OECs but not Schwann cells; some are expressed by olfactory nerve layer OECs but not olfactory mucosal OECs, while some are expressed by olfactory mucosal OECs and Schwann cells but not olfactory nerve layer OECs. For a subset of the genes, I was also able to analyse OEC differentiation in mouse mutants. I also collected transcriptome data from neural crest-derived cells that persist on the olfactory nerve in Sox10-null embryos (in which neural crest-derived cells colonise the olfactory nerve, but normal OEC differentiation is disrupted). Comparison with wild-type OEC transcriptome data from the same embryonic stage identified genes whose expression is likely either downregulated or up-regulated in the absence of Sox10, supporting a role in normal OEC differentiation. Overall, these various transcriptomic comparisons (between OECs at different developmental stages, different OEC subpopulations, OECs versus Schwann cells, and OECs versus Sox10-null neural crest-derived cells on the olfactory nerve) have identified multiple transcription factor and signalling pathway genes, amongst others, that are expressed during OEC development in vivo (including some specific to different OEC subpopulations) and that may be important for OEC differentiation. Furthermore, some of these genes are not expressed by embryonic Schwann cells. This work provides a foundation for understanding how to promote OEC rather than Schwann cell differentiation from neural crest stem cells in culture, with the potential for clinical application in the future.

Alginate hydrogel made from alginate and crosslinking divalent ions is a natural biomaterial that is biocompatible, has low toxicity, is relatively cheap and has mild gelation chemistry. It is a porous material that allows diffusion of small molecules. Alginate hydrogel is a polymeric network that contains 95-99% water and it does in many ways resemble the natural extracellular matrix (ECM) that surrounds cells in the body. It is also hydrophilic, which reduces friction in body fluids and minimizes protein adsorption and it is easily stored and sterilized.Alginate is produced by both algae and bacteria, and it is initially synthesized as mannuronan (M) with 100% M-residues. Guluronic acid residues (G) are introduced in a post-polymerization step by enzymes called mannuronan C-5 epimerases that catalyze conversion of M into G without breaking the glycosidic bond. Seven different mannuronan C-5 epimerases have been sequenced, cloned and produced recombinantly, and these enzymes introduce MG-blocks, G- blocks or both in the alginate chains. With the use of these mannuronan C-5 epimerases it is now possible to engineer alginate with desired and known structure. It is also possible to covalently modify alginates with coupling of cell specific adhesion molecules to the carboxylic group in the monomers. An example is the RGD peptide (arginine-glycine-aspartic acid) that is commonly found in collagen and fibronectin in the ECM. The RGD peptide is the smallest sequence that integrin receptors can recognize and bind to.Central nervous system (CNS) damage is still one of the major causes of both death and disability, despite intense research efforts to achieve neurogenesis and restore functional synaptic connection of CNS neurons. None of he current therapy strategies promote regeneration or regrowth of neural cells or axons. In vitro and in vivo studies has shown that CNS axons can regenerate when located in a permissive environment and it is known that on-going neurogenesis occurs in certain areas of the adult brain, such as the olfactory bulb. Olfactory ensheathing cells (OECs) are found in the olfactory mucosa and olfactory bulb and secrete neurotrophins, provide necessary ECM molecules and substrates for axon elongation and myelination. They do not activate and induce inhibitory molecules or hypertrophy in astrocytes, and are therefore believed to be a promising candidate for cell-mediated repair of the CNS.The major aims of this study was to investigate whether encapsulation of OECs in different types of alginate matrices would improve cell viability over time and induce change of cell morphology, as a future goal is to transplant OECs into the CNS. Viability of OECs up to 14 days in 1.8% UP-LVG capsules have been reported by Kristin Karstensen (Karstensen, 2010), and similar results were achieved in an experiment in this project. Indications of cell concentration dependency on viability were observed in this experiment, with higher viability in capsules with low cell concentration (1.5 mil cells/mL alginate, 3.0 and 5.0 mil/mL). It was decided to conduct an encapsulation of high and low OEC concentration (4.0 mil/mL and 1.0 mil/mL) in 1.0% UP-LVG Ca2+/Ba2+ alginate, with the aim of examining whether reduced alginate concentration would improve cell viability. The results were promising, with a live cell percentage of 50% in the low cell concentration batch after 51 days. The high cell concentration batch was discarded after 22 days with estimated 30% live cells. This result strengthened the hypothesis that lower cell concentration enhanced cell viability, and confirmed that lower alginate concentration improved cell viability notably. These indications were supported by the results of a second encapsulation with similar settings. High and low concentrations (1.5 mil/mL and 5.0 mil/mL) of OECs were encapsulated in 1.0% epimerized Ca2+ alginate with and without 0.2 % RGD peptide graft. The experiment did not show an effect of the RGD peptide on cell viability or morphology. The viability of the cells was extended with one week and viable cells could be observed for 22 days, but in this experiment increased viability as a result of lower cell concentration was less pronounced. This experiment was therefore inconclusive in terms of improved viability connected to cell concentration, but indicated that a lower alginate concentration had a beneficial impact on cell viability. Star shaped channels were observed inside all capsules in this experiment, and a large fraction of dead cells were found to be located inside these channels. This experiment was later repeated with another source of epimerized alginate grafted with ≈ 0.4% RGD peptide with comparable results in terms of cell viability and morphology.Two encapsulations of low cell concentration in 1.0% UP-LVG Ca2+/Ba2+ alginate mixed with three different concentrations of gelatin (0.5%, 1.0% and 2.0%) were carried out, with the aim of observing capsule stability and cell viability. In first experiment the capsule stability appeared to be inversely proportional with gelatin concentration. This was not confirmed when the experiment was repeated, as the batch with the middle gelatin concentration was perceived as most stable. The cell viability was overall high for both encapsulations. Finally, four batches of 1.5 mil/mL OECs were encapsulated in 0.9% UP-LVG Ca2+/Ba2+ alginate gel with one type of ECM molecule mixed with the alginate per batch to yield a concentration of 1.0 mg/mL. Sulphated MG alginate was mixed with 0.9% UP-LVG Ca2+/Ba2+ alginate to a final concentration of 1.0 mg/mL, and included in the experiment. The experiment was terminated at day 28, with varying cell viabilities in the different batches. Common for all was overall lower cell viability compared with the viability observed for cells with similar concentration encapsulated in pure 1.0% UP-LVG, but the capsules proved to be relatively stable. In conclusion, reducing the alginate concentration from 1.8% to 1.0% had notable positive effect on cell viability. High cell concentration in the alginate capsules also proved to have a negative impact on cell viability, but this effect was most evident in the UP-LVG alginate gels. The negative effect on cell viability related to high cell concentration was not as profound in the epimerized alginate gels.RGD peptide grafted onto alginate did not show any unambiguous effect on cell viability and no effect on cell morphology, regardless of 0.2 % peptide graft or ≈ 0.4% peptide graft. The gelatin-1.0% UP-LVG alginate mixes also failed to induce morphology change in the OECs, and neither did any of the ECM molecule-1.0% UP-LVG alginate mixes or the sulphated alginate-1.0% UP-LVG alginate mix. The cells encapsulated in gelatin-alginate mix capsules displayed an overall high viability, while the cells encapsulated in ECM molecule- alginate mix and sulphated alginate- alginate mix displayed lower viability than cells encapsulated in pure UP-LVG alginate. All capsule varieties displayed generally good stability in culture, with the exception of the gelatin-alginate mix capsules that progressively dissolved in culture.

Olfactory ensheathing cells have well described neurotrophic properties and can promote repair of damaged nerves in the central nervous system. Genetically engineering these cells to deliver therapeutic proteins could ‘supercharge’ their existing abilities to repair damaged nerves and prevent neurodegeneration in disease. The present study used retroviral vectors to engineer human olfactory ensheathing cells to co-express the potent neurotrophin GDNF and reporter genes under a tetracycline-inducible promoter. The goal here was to provide proof of concept for using olfactory ensheathing cells (OECs) for controlled ex vivo delivery of GDNF in preclinical studies. Until now, OECs from the olfactory mucosa have not been examined or developed for this purpose. Here a systematic evaluation of OECs revealed their suitability for developing ex vivo gene therapies. Olfactory ensheathing cells from rats and humans were successfully purified from the olfactory mucosa by p75NTR immunopanning and did not express secreted GDNF protein prior to genetic modification. The immunopanning method did not purify putative neural precursors or stem cells from the human source tissue. Lentiviral vectors incorporating bi-cistronic gene expression cassettes directed drug-inducible co-expression of GDNF and reporter gene in transduced OECs. Here for the first time the foot and mouth disease virus 2A cleavage factor was used to co-express GDNF and reporter genes in human OECs. Biological activity of GDNF and reporter genes (EGFP and β-Galactosidase) was not affected by 2A cleavage in transduced OECs. Owing to robust reporter gene expression in these cells, highly purified cultures of drug-inducible and constitutive expressing OECs were isolated by fluorescence activated cell sorting. In the inducible cell lines, more than 20-fold induction of gene expression was seen after treatment with minocycline however, unsatisfactory baseline expression or ‘leakage’ was observed in the absence of minocycline. Cells constitutively co-expressing GDNF and EGFP were then transplanted into the intact rat striatum. After 9 days, transplanted OECs expressed transgenes, but the majority of grafted cells died. Overcoming the poor cell survival and leakage of expression in inducible cells must precede transplanting these cells in animal models of disease. In conclusion, a robust method for co-expressing therapeutic genes in OECs for preclinical ex vivo gene therapy studies was developed using 2A cleavage and lentiviral vectors. The results present a strong case for using OECs as vehicles to deliver therapeutic genes but also highlight shortcomings of drug-inducible gene expression systems.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Science, Environment, Engineering and Technology
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The rat model of cervical dorsal root injury mimics the avulsion of dorsal roots in humans following brachial plexus injury, a condition that leads to debilitating sensory disturbances and intractable neuropathic pain that is not amenable to repair. This injury disrupts sensory inputs from the dorsal roots to the spinal cord and the damaged axons do not regenerate across the PNS-CNS interface, the dorsal root entry zone. This thesis investigated the role of OECs for repairing DRI-associated neuropathic pain, which has never been previously explored. Chapter 2 of this thesis characterised two DRI models, a partial (2-root) or complete (4-root) deafferentation of the rat forepaw. The 2-root animals developed persistent allodynia and hyperalgesia, whereas in the 4-root DRI, in contrast, reduced sensation (desensitisation) was found within the affected forepaw. The degree of deficits on performing complex, skilled forepaw movements was proportional to the severity of DRI. Sensory control of forepaw movements was permanently abolishes in animals with 4-root DRI. With the goal of repairing DRI-associated neuropathic pain, the efficacy of genetically modified OECs that carry a novel GDNF construct was examined. These modified GDNF-OECs were able to produce GDNF in vitro, however, died rapidly and failed to yield long term GDNF expression after both acute and delayed transplantation into the DRI spinal cord. Unmodified plain OECs were then used. The results show that delayed transplantation of OECs attenuated the development of DRI-associated allodynia and hyperalgesia. Central reorganisations occurred within the dorsal horn following DRI, including reduction in the area of deep dorsal horn, permanent depletion of IB4-labeled axons and restoration of CGRP-labelled afferents in the denervated superficial laminae. The development of neuropathic pain is suggested to be mediated by the aberrant expansion of large myelinated VGLUT1-positive afferents into the superficial laminae, which normally receive nociceptive inputs. The effect of OECs on modulating nociception seems to be mediated by factors other than inhibition of afferent sprouting. In conclusion, the results in this thesis demonstrated the potential effect of OECs for modulating DRI-associated neuropathic pain. This finding could have clinical applicability for resistant pain sequelae resulting from neurotrauma.

Phagocytosis (“cell eating”) is an immunobiological process required for maintenance of systemic homoeostasis under normal physiological conditions (during development and adulthood) and in various pathologies. Phagocytosis is a receptor-mediated event, wherein a phagocytic cell recognizes, engulfs and degrades specific targets that need to be eliminated. The targets can be either “self-targets”, such as dead or damaged cells, or “non-self-targets”, such as microorganisms. In the nervous system, the “first responding” phagocytes are usually the supporting glial cells. Based on the location they are present in, glial cells are classified as either CNS or PNS glia. The key phagocytic glia in the CNS are astrocytes and microglia, and in the PNS, Schwann cells (SCs). Some peripheral nerves, however, have other glial types which mediate this function, such as olfactory ensheathing cells (OECs) in the olfactory nerve. Efficient phagocytosis is essential for regeneration after nervous system injury, but after CNS injury, glial phagocytosis is often inefficient. In contrast, after PNS injury, glia rapidly phagocytose and clear the cellular and myelin debris resulting from the injury. Due to their ability to support nerve growth, particularly via physical support and secretion of growth/guidance factors, while simultaneously performing phagocytosis; transplantation of SCs and OECs have promising potential to treat CNS injuries. However, phagocytosis is a highly specialized function and the key molecular and cellular components in PNS glial phagocytosis are largely unknown. If these could be characterized, new drug targets may be revealed that can further promote glial-mediated neural regeneration (but without causing an excessive inflammatory response). The site of a CNS injury is a complex environment, with cell death occurring via different mechanisms. These include distinct types of necrosis and apoptosis, and glia may respond differently to these distinct “self-targets”. Hence, in this Thesis, I investigated key cellular and molecular mechanisms involved in OEC- and SC-mediated phagocytosis of cells undergoing various forms of death. I discovered that OECs and SCs are indeed competent phagocytes that can recognize, internalize and degrade a range of “self-targets”. Both cell types expressed a number of phagocytic receptors, including phosphatidylserine (PS) recognition receptors, pathogen recognition receptors (PRRs), scavenger receptors, Fcγ receptors (FcγRs) and complement receptors (CRs). OECs and SCs both rapidly recognised and engulfed various cellular targets (within 2 h). Recognition of targets occurred mainly via PS displayed on the dying cell surface, with potential involvement of PRRs. The family of small Rho GTPases (Rac, Cdc42 and Rho) were also important for target engulfment. However, while engulfment was rapid, breakdown was relatively slow, particularly when the targets were necrotic bodies and myelin debris (especially when compared to professional phagocytes, i.e., macrophages). Engulfment of apoptotic targets resulted in anti-inflammatory cytokine production, however, necrotic target uptake led to a proinflammatory response. Overall, OECs phagocytosed larger amounts of targets over time, as well as processed targets faster, than SCs. During the process of phagocytosis, OECs also produced less pro-inflammatory, but more immunomodulatory, factors than SCs. Thus, OECs were more efficient in phagocytosing “self-targets” than SCs, accompanied by a more favourable immune response, suggesting that OECs may be better transplantation candidates than SCs. Two peripheral nerves, the olfactory nerve and the trigeminal nerve (intranasal branches) extend between the nasal cavity and the brain. These nerves are populated by OECs and SCs, respectively. These nerves have been shown to function as a pathway by which certain microbes can enter the brain, leading to CNS infection. The nasal mucosa, and associated nasal-associated lymphoid tissue (NALT) constitute a strong physical and immunological barrier against microorganisms, and those that do manage to penetrate the mucosa are considered to be phagocytosed by OECs and SCs in the nerves. However, microbes that can infect the CNS via these two peripheral nerves have been shown to evade phagocytic destruction and instead infect PNS glia. In this Thesis, I also investigated how OECs and SCs respond to bacterium thought to infect the CNS via nerves - Chlamydia muridarum. I chose this bacterium as it is commonly used to model C. pneumoniae infections in mice. C. pneumoniae CNS infection has been suggested to contribute to the development of late-onset dementia, thus being clinically relevant. I found that C. muridarum, which replicates in intracellular inclusion bodies, infected both OECs and SCs, however, the glia were not as susceptible to infection and intracellular bacterial growth as non-immune cells. Both OECs and SCs mounted a significant immune response to bacterial challenge, with OECs producing the strongest response. Despite this, C. muridarum could manipulate various intracellular and phagocytic machinery pathways to survive inside the glia, including pathways involving small Rho GTPases (Rac, Cdc42 and Rho) and PI3K/Akt. C. muridarum also suppressed lysosomal recruitment by “hijacking” Ras-like small GTPases (Rabs) responsible for intracellular trafficking and host nutrient scavenging. Thus, C. muridarum could escape phagocytosis (degradation) and grow inside glia. This is potentially a key reason by which the bacteria may disseminate through peripheral nerves, leading to CNS infection. The findings presented in this Thesis (including resultant publications), increases our understanding of how PNS glia remove dying and damaged “self”, including key cellular and molecular mechanisms involved in OEC and SC-mediated phagocytosis. The current study also, by characterizing how the glia responded to C. muridarum, explored the crucial dichotomy between phagocytosis vs infection. Internalization of bacteria into a cell can lead to either or both. In the case of OECs and SCs, C. muridarum challenge led to infection but also an immune response, restricted bacterial growth and likely also killing of a proportion of bacteria. This understanding may provide us with tools/drug targets for manipulation of various aspects of the PNS glia-mediated phagocytic processes. This could involve improved clearance of cellular debris without adverse inflammatory events post-transplantation into a nervous system injury site. Tweaking certain aspects of the phagocytic pathway may also prevent infections by microbes that can use the nose-to-brain pathway to infect the CNS, without using antibiotics (thus, not contributing to antimicrobial resistance). Finally, this thesis has also given us some interesting insights into differences between the two types of PNS glia. OECs and SCs, were considered to be quite similar in the past and both are deemed as good transplantation candidates. Overall, OECs were found to be more efficient phagocytes and equipped with additional molecular components of phagocytic pathways than SCs. OECs also produced a more favourable immune response than SCs in response to damaged “self”. In contrast, OECs mounted a stronger bactericidal immune response to C. muridarum than SCs, suggesting that OECs exhibit better antimicrobial protection mechanisms than SCs.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Pharmacy & Med Sci
Griffith Health
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