ORCID Profile
0000-0002-3739-1688
Current Organisation
University of Queensland
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Cellular Nervous System | Central Nervous System | Medical Biotechnology | Biomaterials | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Cell Development, Proliferation and Death | Neurosciences
Expanding Knowledge in the Biological Sciences | Health Related to Ageing | Expanding Knowledge in Engineering |
Publisher: Wiley
Date: 19-09-2009
DOI: 10.1002/GLIA.20771
Abstract: The primary olfactory pathway in adult mammals has retained a remarkable potential for self-repair. A specialized glial cell within the olfactory nerve, called olfactory ensheathing cell (OEC), and their associated extracellular matrix are thought to play an important role during regenerative events in this system. To gain insight into novel molecules that could mediate the OEC-supported growth of axons within the olfactory nerve, gene expression profiling experiments were conducted which revealed high expression of the glycoprotein fibulin-3 in OECs. This observation was confirmed with quantitative PCR. In vivo, the distribution of all members of the fibulin family, fibulin-3 included, was localized to the lamina propria underneath the olfactory epithelium, in close association within olfactory nerve bundles. To manipulate fibulin-3 gene expression in cultured OECs, lentiviral vector constructs were designed to either transgenically express or knock-down fibulin-3. Experimental data showed that increased levels of fibulin-3 induced profound morphological changes in cultured OECs, impeded with their migratory abilities and also suppressed OEC-mediated neurite outgrowth. Knock-down of fibulin-3 levels resulted in reduced OEC proliferation. In conclusion, the data provide novel insights into a putative role for fibulin-3 in the regulation of cell migration and neurite outgrowth within the primary olfactory pathway.
Publisher: Cambridge University Press (CUP)
Date: 05-2007
DOI: 10.1017/S1740925X07000671
Abstract: We used an in vivo transplant approach to examine how adult Schwann cells and olfactory ensheathing glia OEG influence the specificity of axontarget cell interactions when they are introduced into the CNS. Populations of either Schwann cells or OEG were mixed with dissociated fetal tectal cells presumptive superior colliculus and, after reaggregation, pieces were grafted onto newborn rat superior colliculus. Both glial types were prelabeled with lentiviral vectors encoding green fluorescent protein. Grafts rapidly established fiber connections with the host and retinal projections into cografts were assessed 656 days posttransplantation by injecting cholera toxinB into host eyes. In control rats that received pure dissociatedreaggregated tectal grafts, retinal ganglion cell RGC axons selectively innervated defined target areas, corresponding to the retinorecipient layer in normal superior colliculus. The pattern of RGC axon ingrowth into OEG containing cografts was similar to that in control grafts. However, in Schwann cell cografts there was reduced host retinal input into presumptive target areas and many RGC axons were scattered throughout the neuropil. Given that OEG in cografts had minimal impact on axontarget cell recognition, OEG might be an appropriate cell type for direct transplantation into injured neuropil when attempting to stimulate specific pathway reconstruction.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Public Library of Science (PLoS)
Date: 27-11-2012
Publisher: Elsevier BV
Date: 03-2023
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.MATBIO.2009.06.001
Abstract: The adult olfactory epithelium has maintained the ability to reconstitute its olfactory sensory neurons (OSNs) from a basal progenitor cell compartment. This allows for life-long turnover and replacement of receptor components as well as repair of the primary olfactory pathway in response to injury and environmental insults. The present study investigated whether fibulin-3, a glycoprotein in the extracellular matrix and binding partner of tissue inhibitor of metalloproteinases-3 (TIMP-3), plays a role in ongoing plasticity and regenerative events in the adult primary olfactory pathway. In wild-type control mice, fibulin-3 protein was detected on IB4(+)CD31(+) blood vessels, nerve fascicles and the basement membrane underneath the olfactory epithelium. After target ablation (olfactory bulbectomy), fibulin-3 was also abundantly present in the central nervous system (CNS) scar tissue that occupied the bulbar cavity. Using two different lesion models, i.e. intranasal Triton X-100 lesion and olfactory bulbectomy, we show that fibulin-3 deficient (Efemp1(-/-)) mice have impaired recovery of the olfactory epithelium after injury. Ten days post-injury, Efemp1(-/-) mice showed altered basal stem rogenitor cell proliferation and increased overall numbers of mature (olfactory marker protein (OMP) -positive) versus immature OSNs. However, compromised regenerative capacity of the primary olfactory pathway in Efemp1(-/-) mice was evidenced by reduced numbers of mature OSNs at the later time point of 42 days post-injury. In addition to these neural differences there were consistent changes in blood vessel structure in the olfactory lamina propria of Efemp1(-/-) mice. Overall, these data suggest a role for fibulin-3 in tissue maintenance and regeneration in the adult olfactory pathway.
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 03-2020
Publisher: Society for Neuroscience
Date: 09-05-2012
DOI: 10.1523/JNEUROSCI.5925-11.2012
Abstract: Exercise has been shown to positively augment adult hippoc al neurogenesis however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippoc al microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippoc al cultures. Conversely, microglia from the hippoc i of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX 3 CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blocking antibody against the CX 3 CL1 receptor, CX 3 CR1, but not control IgG, dramatically reduced the neurosphere formation frequency in mice that had exercised. While an increase in soluble CX 3 CL1 was observed following running, reduced levels of this chemokine were found in the aged brain. Lower levels of CX 3 CL1 with advancing age correlated with the natural decline in neural precursor cell activity, a state that could be partially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippoc us, and that signaling through the CX 3 CL1–CX 3 CR1 axis critically contributes toward this process.
Publisher: Public Library of Science (PLoS)
Date: 02-12-2011
Publisher: Wiley
Date: 25-05-2016
DOI: 10.1002/ACN3.318
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.BRAINRESBULL.2017.05.013
Abstract: Birth of new neurons in the hippoc us persists in the brain of adult mammals and critically underpins optimal learning and memory. The process of adult neurogenesis is significantly reduced following brain irradiation and this correlates with impaired cognitive function. In this study, we aimed to compare the long-term effects of two environmental paradigms (i.e. enriched environment and exercise) on adult neurogenesis following high-dose (10Gy) total body irradiation. When housed in standard (sedentary) conditions, irradiated mice revealed a long-lasting (up to 4 months) deficit in neurogenesis in the granule cell layer of the dentate gyrus, the region that harbors the neurogenic niche. This depressive effect of total body irradiation on adult neurogenesis was partially alleviated by exposure to enriched environment but not voluntary exercise, where mice were single-housed with unlimited access to a running wheel. Exposure to voluntary exercise, but not enriched environment, did lead to significant increases in microglia density in the granule cell layer of the hippoc us our study shows that these changes result from local microglia proliferation rather than recruitment and infiltration of circulating Cx
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.JNEUROIM.2008.09.010
Abstract: The olfactory epithelium (OE) is a site of massive adult neurogenesis where olfactory sensory neurons (OSNs) are continuously turned over. Tissue macrophages have been implicated in phagocytosis of degenerating cells but the molecular mechanisms that allow for their recruitment while maintaining a neurogenic microenvironment are poorly understood. This study reports that the neuroprotective chemokine CX3CL1 is expressed by OSNs and olfactory ensheathing cells. Monocyte-derived cells in the OE depend on CX3CL1-signalling for intraepithelial migration and apical dendrite expression. These observations are first to demonstrate phenotypic differences in appearance and distribution of monocyte-derived cells in nervous tissue due to CX3CR1 deficiency.
Publisher: Cold Spring Harbor Laboratory
Date: 11-02-2021
DOI: 10.1101/2021.02.11.430773
Abstract: To support their innate immune and scavenging functions in the brain, microglia are equipped with Toll-like receptors (TLRs), including the intracellular receptor TLR9, which is activated by microbial CpG-rich DNA. Macropinocytosis is an abundant and inducible pathway in microglia for fluid-phase uptake and ingestion of microbes and cell debris. TLR9 signaling has been ascribed to endolysosomes, particularly lysosomes, which it accesses through direct transport or via internalization from the surface. Here, TLR9 and exogenous CpG-DNA are localized during uptake into fluid-filled macropinosomes, upon upregulated macropinocytosis, where acidic and proteolytic environments support MyD88-induced signaling. Macropinosomes represent an abundant pathway for endolysosomal traffic of TLR9 but are also a much more exposed site for nucleic acid activation of the receptor with a risk of excessive inflammation. To constrain TLR9 inflammation, macropinosomes also house the TLR9 co-receptor LRP1 and regulators Rab8a and PI3Kγ which augment Akt signaling and favor anti-inflammatory cytokine production. Macropinosomes and their inflammatory regulators are therefore important components of TLR9 pathways in microglia that are poised for surveillance and protection in the CNS.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2017
DOI: 10.1038/S41598-017-12583-1
Abstract: Activated neurons express immediate-early genes, such as Arc. Expression of Arc in the hippoc al granule cell layer, an area crucial for spatial learning and memory, is increased during acquisition of spatial learning however, it is unclear whether this effect is related to the task-specific learning process or to nonspecific aspects of the testing procedure (e.g. exposure to the testing apparatus and exploration of the environment). Herein, we show that Arc-positive cells numbers are increased to the same extent in the granule cell layer after both acquisition of a single spatial learning event in the active place avoidance task and exploration of the testing environment, as compared to naïve (i.e. caged) mice. Repeated exposure the testing apparatus and environment did not reduce Arc expression. Furthermore, Arc expression did not correlate with performance in both adult and aged animals, suggesting that exploration of the testing environment, rather than the specific acquisition of the active place avoidance task, induces Arc expression in the dentate granule cell layer. These findings thus suggest that Arc is an experience-induced immediate-early gene.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.MCN.2011.08.004
Abstract: The olfactory epithelium is a site of sustained adult neurogenesis where olfactory sensory neurons are continuously replaced from endogenous stem rogenitor cells. Epithelial macrophages have been implicated in the phagocytosis of degenerating cells but the molecular mechanisms allowing for their recruitment and activation while maintaining a neurogenic microenvironment are poorly understood. We have previously shown that the chemokine fractalkine (CX₃CL1) is expressed by olfactory sensory neurons and ensheathing cells in the olfactory epithelium. In turn, the fractalkine receptor, CX₃CR1, is expressed on macrophages and dendritic cells within the olfactory epithelium. We report that a selective cell death of olfactory sensory neurons in the epithelium of CX₃CR1-deficient mice via target ablation (i.e. olfactory bulbectomy) results in an exacerbated loss of olfactory sensory neurons compared to wild-type mice. In addition, reduced proliferation of intraepithelial stem rogenitor cells was observed in lesioned CX₃CR1-deficient mice, suggesting an impaired regenerative response. Importantly, a lack of CX₃CL1-signaling caused increased recruitment of macrophages into the olfactory epithelium, which in turn contained higher levels of pro-inflammatory cytokines (e.g. TNF-α and IL-6) as determined by qPCR. We also present novel data showing that, relative to wild-type, CX₃CR1-deficient macrophages have diminished phagocytic activity following stimulation with CX₃CL1. Collectively, our data indicate that signaling through the CX₃CR1 receptor modulates macrophage activity, resulting in an environment conducive to olfactory sensory neuron clearance and targeted replacement from endogenous stem rogenitor cells.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Frontiers Media SA
Date: 17-10-2017
Publisher: Elsevier BV
Date: 09-2023
Publisher: Wiley
Date: 06-12-2013
DOI: 10.1002/GLIA.22603
Abstract: Microglia positively affect neural progenitor cell physiology through the release of inflammatory mediators or trophic factors. We demonstrated previously that reactive microglia foster K(ATP) -channel expression and that blocking this channel using glibenclamide administration enhances striatal neurogenesis after stroke. In this study, we investigated whether the microglial K(ATP) -channel directly influences the activation of neural precursor cells (NPCs) from the subventricular zone using transgenic Csf1r-GFP mice. In vitro exposure of NPCs to lipopolysaccharide and interferon-gamma resulted in a significant decrease in precursor cell number. The complete removal of microglia from the culture or exposure to enriched microglia culture also decreased the precursor cell number. The addition of glibenclamide rescued the negative effects of enriched microglia on neurosphere formation and promoted a ∼20% improvement in precursor cell number. Similar results were found using microglial-conditioned media from isolated microglia. Using primary mixed glial and pure microglial cultures, glibenclamide specifically targeted reactive microglia to restore neurogenesis and increased the microglial production of the chemokine monocyte chemoattractant protein-1 (MCP-1). These findings provide the first direct evidence that the microglial K(ATP) -channel is a regulator of the proliferation of NPCs under inflammatory conditions.
Publisher: Mary Ann Liebert Inc
Date: 04-2006
Abstract: Injured neurons in the mammalian central nervous system (CNS) do not normally regenerate their axons after injury. Neurotrauma to the CNS usually results in axonal damage and subsequent loss of communication between neuronal networks, causing long-term functional deficits. For CNS regeneration, repair strategies need to be developed that promote regrowth of lesioned axon projections and restoration of neuronal connectivity. After spinal cord injury (SCI), cystic cavitations are often found, particularly in the later stages, due to the loss of neural tissue at the original impact site. Ultimately, for the promotion of axonal regrowth in these situations, some form of transplantation will be required to provide lesioned axons with a supportive substrate along which they can extend. Here, we review the use of olfactory ensheathing cells: their location and role in the olfactory system, their use as cellular transplants in SCI paradigms, alone or in combination with gene therapy, and the unique properties of these cells that may give them a potential advantage over other cellular transplants.
Publisher: Society for Neuroscience
Date: 30-03-2021
DOI: 10.1523/JNEUROSCI.2539-20.2021
Abstract: Microglia, the resident immune cells of the CNS, have emerged as key regulators of neural precursor cell activity in the adult brain. However, the microglia-derived factors that mediate these effects remain largely unknown. In the present study, we investigated a role for microglial brain-derived neurotrophic factor (BDNF), a neurotrophic factor with well known effects on neuronal survival and plasticity. Surprisingly, we found that selective genetic ablation of BDNF from microglia increased the production of newborn neurons under both physiological and inflammatory conditions (e.g., LPS-induced infection and traumatic brain injury). Genetic ablation of BDNF from microglia otherwise also interfered with self-renewal roliferation, reducing their overall density. In conclusion, we identify microglial BDNF as an important factor regulating microglia population dynamics and states, which in turn influences neurogenesis under both homeostatic and pathologic conditions. SIGNIFICANCE STATEMENT (1) Microglial BDNF contributes to self-renewal and density of microglia in the brain. (2) Selective ablation of BDNF in microglia stimulates neural precursor proliferation. (3) Loss of microglial BDNF augments working memory following traumatic brain injury. (4) Benefits of repopulating microglia on brain injury are not mediated via microglial BDNF.
Publisher: Society for Neuroscience
Date: 10-04-2013
DOI: 10.1523/JNEUROSCI.3064-12.2013
Abstract: It is now widely accepted that hippoc al neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippoc al neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.
Publisher: American Society of Hematology
Date: 03-03-2022
Abstract: Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippoc us identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II+ donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.NEUINT.2011.04.003
Abstract: The generation of new neurons within the dentate gyrus of the mature hippoc us is critical for spatial learning, object recognition and memory, whereas new neurons born in the subventricular zone (SVZ) contribute to olfactory function. Adult neurogenesis is a multistep process that begins with the activation and proliferation of a pool of stem recursor cells. Although the presence of self-renewing and multipotent neural precursors is well established in the SVZ, it is only recently that the existence of such a precursor population has been demonstrated in the hippoc us, the region of the brain involved in learning and memory. Determining how this normally latent pool can be activated therefore offers considerable potential for the development of targeted neurogenic-based therapeutics to ameliorate the cognitive decline associated with hippoc al dysfunction in several neurodegenerative diseases. In this review, we summarize the effects of neural activity, various molecular factors and pharmaceutical agents, as well as voluntary exercise, in activating endogenous neural precursors in the two neurogenic niches of the adult brain, and highlight the role of activation-driven enhancement of neurogenesis for the treatment of psychiatric illness and aging dementia.
Publisher: Oxford University Press (OUP)
Date: 07-07-2010
DOI: 10.1189/JLB.0410194
Abstract: Definition of the heterogeneity of monocyte-derived cells in the neurogenic olfactory neuroepithelium, their turnover, and the role of CX3CR1 in this process. Macrophages in the olfactory neuroepithelium are thought to play major roles in tissue homeostasis and repair. However, little information is available at present about possible heterogeneity of these monocyte-derived cells, their turnover rates, and the role of chemokine receptors in this process. To start addressing these issues, this study used Cx3cr1gfp mice, in which the gene sequence for eGFP was knocked into the CX3CR1 gene locus in the mutant allele. Using neuroepithelial whole-mounts from Cx3cr1gfp/+ mice, we show that eGFP+ cells of monocytic origin are distributed in a loose network throughout this tissue and can be sub ided further into two immunophenotypically distinct subsets based on MHC-II glycoprotein expression. BM chimeric mice were created using Cx3cr1gfp/+ donors to investigate turnover of macrophages (and other monocyte-derived cells) in the olfactory neuroepithelium. Our data indicate that the monocyte-derived cell population in the olfactory neuroepithelium is actively replenished by circulating monocytes and under the experimental conditions, completely turned over within 6 months. Transplantation of Cx3cr1gfp/gfp (i.e., CX3CR1-deficient) BM partially impaired the replenishment process and resulted in an overall decline of the total monocyte-derived cell number in the olfactory epithelium. Interestingly, replenishment of the CD68lowMHC-II+ subset appeared minimally affected by CX3CR1 deficiency. Taken together, the established baseline data about heterogeneity of monocyte-derived cells, their replenishment rates, and the role of CX3CR1 provide a solid basis to further examine the importance of different monocyte subsets for neuroregeneration at this unique frontier with the external environment.
Publisher: Springer Science and Business Media LLC
Date: 06-11-2020
DOI: 10.1038/S41598-020-76176-1
Abstract: Hippoc al atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. To determine whether cognitive decline can be ameliorated by exercise-induced neurogenesis, C57BL/6 mice in which a unilateral hippoc al injury had been induced by injecting the vasoconstrictor endothelin-1 into their right hippoc us, were run voluntarily for 21 days on a running-wheel. We found the severe deficits in spatial learning, as detected by active place-avoidance task, following injury were almost completely restored in animals that ran whereas those that did not run showed no improvement. We show the increase in neurogenesis found in both the injured and contralateral hippoc i following running was responsible for the restoration of learning since bilateral ablation of newborn doublecortin (DCX)-positive neurons abrogated the cognitive improvement, whereas unilateral ablations of DCX-positive neurons did not prevent recovery, demonstrating that elevated neurogenesis in either the damaged or intact hippoc us is sufficient to reverse hippoc al injury-induced deficits.
Publisher: Public Library of Science (PLoS)
Date: 04-09-2012
Start Date: 2015
End Date: 07-2018
Amount: $372,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 01-2018
End Date: 12-2019
Amount: $270,427.00
Funder: Australian Research Council
View Funded Activity