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Distasio, Andrew. "Novel Regulators of Neural Crest and Neural Progenitor Survival." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1593170783550813.
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Farnsworth, Dylan. "Temporal changes in neural progenitor competence." Thesis, University of Oregon, 2017. http://hdl.handle.net/1794/22280.
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Drosophila neural stem cells (neuroblasts) are a powerful model system for investigating stem cell self-renewal, specification of temporal identity, and progressive restriction in competence. Notch signaling is a conserved cue that is an important determinant of cell fate in many contexts across animal development; for example mammalian T cell differentiation in the thymus and neuroblast specification in Drosophila are both regulated by Notch signaling. However, Notch also functions as a mitogen, and constitutive Notch signaling potentiates T cell leukemia as well as Drosophila neuroblast tumors. While the role of Notch signaling has been studied in these and other cell types, it remains unclear how stem cells and progenitors change competence to respond to Notch over time. Notch is required in type II neuroblasts for normal development of their transit amplifying progeny, intermediate neural progenitors (INPs). Here we find that aging INPs lose competence to respond to constitutively active Notch signaling. Moreover, we show that reducing the levels of the old INP temporal transcription factor Eyeless/Pax6 allows Notch signaling to promote the de-differentiation of INP progeny into ectopic INPs, thereby creating a proliferative mass of ectopic progenitors in the brain. These findings provide a new system for studying progenitor competence, and identify a novel role for the conserved transcription factor Eyeless/Pax6 in blocking Notch signaling during development.
This dissertation includes previously published, co-authored material
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Leeson, Hannah Caitlin. "P2X7 Receptor Regulation of Hippocampal Neural Progenitor Cells." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/373045.
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Adult hippocampal neurogenesis plays an essential role in the formation and consolidation of new memories, spatial processing and some forms of learning. Identifying the molecular mechanisms that regulate hippocampal neural progenitor cells as they proliferate, differentiate, and are selected for either survival or cell death will provide a fundamental understanding of how this neurogenic niche coordinates these activities. Here, the roles of P2X7 receptors are examined for their influence over neural progenitor cell biology, particularly cell death, proliferation, and phagocytosis of apoptotic progenitors that have undergone programmed cell death. As a purinergic cation channel, P2X7 receptors are exceptionally versatile; their primary role is as ATP-gated calcium channels, and they have notable roles in the immune system, where they regulate cytokine release and form large transmembrane pores resulting in cell death. By acting as scavenger receptors, they can also mediate phagocytosis. These diverse roles were investigated in neural progenitor cells of the adult murine hippocampal neurogenic niche.
Primary cultures of hippocampal neural progenitor cells were derived from adult female C57BL/6 mice and characterised using multimarker immunocytochemistry as P2X7 receptor positive type 2 neural progenitor cells, as defined by Sox2pos, nestinpos, BLBPpos, Mash1pos/neg, vimentinpos, Pax6pos, Prox1pos, DCXneg, GFAPneg staining patterns. For some experiments, cultures derived from P2X7 knock out mice (Pfizer) were also used. Calcium influx assays using the indicator dye Fluo-8-AM demonstrated functional activity of P2X7 receptors with the general agonist ATP (1 mM) and the more specific agonist BzATP (100 μM). Ethidium bromide uptake demonstrated that P2X7 receptors were able to form large transmembrane pores, a canonical function unique to this receptor, and confirmed the presence of a full length protein, as opposed to various splice variants. Live cell confocal microscopy revealed hippocampal neural progenitors are capable of phagocytosing fluorescent latex beads, and flow cytometry in conjunction with specific inhibitors demonstrated that P2X7 receptors are capable of facilitating this phagocytosis.
The effects of purinergic signalling on neural progenitor proliferation were assessed using the thymidine analogue EdU. P2X7 receptors activated with either extracellular ATP or BzATP showed a significant dose-dependent decrease in proliferation. Cell death was not observed under these conditions and proliferation could be rescued upon exchange of medium. P2X7 receptor inhibition reduced the effects of extracellular ATP on proliferation, and use of neural progenitor cultures derived from genetically null mice corroborated this observation. Convergence with growth factor signalling pathways was also explored.
The data presented here provides good evidence that P2X7 receptors function as scavenger receptors in the absence of ATP, allowing neural progenitor cells to phagocytose their apoptotic peers during target-independent programmed cell death, as well as governing rates of proliferation in the presence of ATP, possibly by regulating calcium dependent downstream signalling. Effector molecules of calcium signalling pathways were investigated following P2X7 receptor activation to determine some of the downstream mechanisms involved in P2X7 receptor mediated decreases in proliferation. Live cell calcium imaging identified the instigation of secondary calcium oscillations following extracellular ATP application; it was hypothesised that the decrease in proliferation was due to calcium dependent signalling cascades, involving calcium release from internal stores. Using confocal microscopy, calcium dependent transcription factors NFκB and NFAT1 were evaluated for their potential to translocate to the nucleus following purinergic stimulation. Extracellular ATP did not cause translocation of NFκB or NFAT1. A possible convergence with growth factor signalling pathways was investigated as the growth factors present in culture conditions exert powerful regulation over the cells and also utilise calcium and endoplasmic reticulum signalling to exert their effects. Inhibition of proteins involved in endoplasmic reticulum signalling caused a decrease in proliferation, as did growth factor withdrawal. Transcription factor analysis revealed that withdrawal of both EGF and bFGF caused NFAT1, but not NFκB, to translocate to the nucleus, a novel finding in these cells.
The data presented here is among the first to examine the dichotomous signalling roles of P2X7 receptors in adult hippocampal neural progenitor cells. In mature neurons, P2X7 receptors have been implicated in various pathologies, and may present a therapeutic target for a number of neurological disorders. Understanding how these receptors regulate the physiology of stem and progenitor cells is an important first step in developing any regenerative therapies. Given the crucial role neurogenesis plays in both memory formation and hippocampal function, understanding these biological mechanisms is essential to addressing significant questions regarding neurogenesis and regeneration.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Nunn, A. C. "The role of SOX9 in neural progenitor identity." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1372652/.
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Recent evidence has shown that SOX9 is required for the proliferation and multipotentiality of neural progenitors in the developing CNS. Notably, these findings suggest that in contrast to previous studies, SOX9 is important for differentiation along the neuronal lineage, both in the adult and embryonic CNS. Here, a phenotypic analysis of the CNS-specific Sox9-null forebrain, including detailed analysis of cortical lamination, shows that neurons of the appropriate layer-identity are born and migrate to their destined layers. All other parameters in this analysis were normal, with the exception of the formation of glia from the ventral and dorsal telencephalons, and midline glial structures, which were absent in the mutant. Since Sox9 is expressed long before the onset of gliogenesis in these brain regions, the possibility that Sox9 may ‘prime’ the progenitors of the ventricular zone to respond to a gliogenic signal arose. To investigate this, populations of Sox9-deficient and wild-type dorsal telencephalon cells were enriched for progenitors and subjected to transcriptional profiling. Bioinformatic analysis revealed that ‘vascular endothelial growth factor’ receptors, which are important for gliogenesis, were down-regulated, in addition to two transcription factors. Previously, Sox9-deficient neural progenitors have been shown to generate neurospheres poorly, and so the dataset of potential targets was used to identify candidates that might mediate this reduced neurosphere-forming ability. Thirteen down-regulated targets were confirmed by qPCR, six of which were expressed in the same distribution as Sox9 in the embryonic telencephalon; three were also expressed in neurosphere cultures. Of these, one encoded a K+ channel (Kir4.1), and the other a modulator of the GABAA channel (DBI). In order to show that reduced expression of one of these might contribute to the Sox9-deficient neurosphere phenotype, pharmacological modulators were used and showed that blockade of Kir4.1 or enhancement of GABAA channels mimicked the effect of Sox9 loss, leaving open the possibility that Kir4.1 or DBI expression might mediate this effect.
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Dause, Tyler. "Investigating Neural Stem and Progenitor Cell Intracrine Signaling." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555618643450352.
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Buscarlet, Manuel. "The neural progenitor to neuron transition : role and regulation of GrouchoTLE proteins." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115670.
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Groucho/transducin-like Enhancer of split (Gro/TLE) family proteins are corepressors found as part of multiple transcriptional complexes that play significant roles during many developmental processes, including neurogenesis. This thesis sought to characterize the molecular mechanisms underlying the biological activity of Gro/TLE1. More specifically, the aim was to clarify the contribution of different transcriptional cofactors, as well as phosphorylation events induced by cofactor binding, to Gro/TLE1 ability to inhibit neuronal differentiation from proliferating neural progenitor cells.By characterizing specific point mutations within the C-terminal domain of Gro/TLE1, we were able to selectively impair binding of Gro/TLE1 to different classes of DNA-binding proteins and then assess the effect of those mutations on Gro/TLE1 anti-neurogenic function. These studies showed that the inhibition of cerebral cortex (cortical) neuron differentiation by Gro/TLE1 requires interaction with transcription factors that use short tetrapeptide sequences, WRP(W/Y), to recruit Gro/TLE1. In contrast, interactions with proteins that either interact with the C-terminal domain of Gro/TLE1 using a different type of binding sequence, termed engrailed homology 1 (Eh1) motif, or bind to the N-terminal part of the protein, are not required for Gro/TLE1 anti-neurogenic function.
Using a similar strategy based on mutation analysis, we characterized point mutations that block the hyperphosphorylation of Gro/TLE1 induced by transcription cofactor binding ("cofactor-activated phosphorylation") without impairing cofactor binding and transcriptional corepression ability. These mutations map at phosphorylatable serine residues, Ser-286, Ser-289, and Ser298. Mutation of those residues to alanine blocks/reduces both cofactor-activated phosphorylation and anti-neurogenic activity of Gro/TLE1, demonstrating that cofactor-activated phosphorylation is required for that function. Tandem mass spectroscopy analysis showed further that Ser-286 is phosphorylated. Taken together, these findings characterize the role of cofactor-activated phosphorylation and identify residues important for this mechanism.
Our studies also showed that homeodomain-interacting protein kinase 2 (HIPK2) mediates phosphorylation of Gro/TLE1 when the latter is complexed with transcriptional partners of the WRP(W/Y) motif family. However, HIPK2 is not involved in Gro/TLE1 cofactor-activated phosphorylation. Rather, HIPK2--mediated phosphorylation is antagonistic to the latter and decreases the ability of Gro/TLE1 to interact and repress transcription with WRP(W/Y) motif proteins.
Taken together, these results improve significantly our understanding of the mechanisms underlying the anti-neurogenic function of Gro/TLE1. This information provides new insight into the regulation of mammalian neuronal development and, possibly, other developmental processes controlled by Gro/TLE proteins.
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Curtis, Maurice A. "Neural progenitor cells in the Huntington's Disease human brain." Thesis, University of Auckland, 2004. http://hdl.handle.net/2292/3114.
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The recent demonstration of endogenous progenitor cells in the adult mammalian brain raises the exciting possibility that these undifferentiated cells may be able to generate new neurons for cell replacement in diseases such as Huntington's disease (HD). Previous studies have shown that neural stem cells in the rodent brain subependymal layer (SEL), adjacent to the caudate nucleus, proliferate and differentiate into neurons and glial cells but no previous study has characterised the human SEL or shown neurogenesis in the diseased human brain. In this study, histochemical and immunohistochemical techniques were used to demonstrate the regional anatomy and staining characteristics of the normal and HD brain SEL using light and laser scanning confocal microscopy. The results demonstrated that the normal and HD SEL contained migrating neuroblasts, glial cells and precursor cells but there were more of each cell type present in the HD brain, and that the increase in cell numbers correlated with HD neuropathological grade. The normal and HD SEL was stained with a proliferative marker, proliferating cell nuclear antigen (PCNA), to label dividing cells. The results showed a significant increase in the number of dividing cells in the HD brain that correlated with HD grade and with CAG repeat length. Furthermore, the results showed that neurogenesis had occurred in the SEL as evidenced by co-localisation of PCNA and the neuronal marker βIII-tubulin. Also, gliogenesis had occurred in the SEL as evidenced by the co-localisation of PCNA with the glial marker GFAP. These studies also revealed a 2.6 fold increase in the number of new neurons in the HD SEL. PCNA positive cells were distributed throughout the SEL overlying the caudate nucleus but most notably the ventral and central regions of the SEL adjacent to the caudate nucleus contained the highest number of proliferating cells. I examined the SEL for mature cell markers and demonstrated many of the same cell types that are present in the normal striatum. With the exception of neuropeptide Y (NPY) neurons, there was a reduction in the number of mature neurons in the HD SEL. The NPY neurons were more abundant in the HD SEL suggesting they play a role in progenitor cell proliferation. The results in this thesis provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and indicate the regenerative potential of the human brain. These findings may be of major relevance to the development of therapeutic approaches in the treatment of neurodegenerative diseases.
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Smith, Edward John. "Establishing a neural progenitor cell model of Huntington's disease." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/establishing-a-neural-progenitor-cell-model-of-huntingtons-disease(5bcdd521-e71a-4dcb-b833-971f32576c2a).html.
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Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene The R6/2 transgenic mouse model exhibits a rapid onset of Huntington's disease-like phenotypes including neurodegeneration and aggregation of mutant huntingtin protein (mHTT). Neural progenitor cells (NPCs) are a pool of cells with stem cell-like properties and are responsible for self-renewal and differentiation into the cells of the central nervous system and mature brain. In this thesis, NPC lines were established from cells extracted from foetal R6/2 and wildtype mouse embryos and cultured in optimised culture media. NPCs were successfully maintained in a mitotic state as monolayer cultures for multiple passages without effects to karyotype or CAG repeat length. Cultures were differentiated by removal of growth factors, into mixed neurons and glia populations that expressed proteins indicative of mature cell types; neurons showed evidence of synaptophysin expression at junctions between cell neurites, suggesting synaptic functionality and formation of rudimentary neural networks. After differentiation, mHTT aggregation was detectable using immunohistochemistry from 14 days of differentiation in 5% of R6/2 cell nuclei, rising to 20% by 28 days, recapitulating an HD-like phenotype found in vivo. Detection of detergent insoluble mHTT-aggregated protein was also validated via western blotting. Super high resolution cell imaging showed aggregation of mHTT is also present in the cytoplasm. High-content imaging analysis system was performed using the Operetta system to explore morphological differences between WT and R6/2 cultures, as well as within the subset of cells with detectable aggregation. R6/2 nuclei were found to be larger than those of WT cells. Novel compounds known to affect protein aggregation were applied to the cell lines to assess their potential use in screening for approaches to modulation mHTT aggregation. The cells developed in this thesis are a novel and useful complement to the R6/2 mouse; phenotypes observed in vivo can be interrogated at the molecular level in terms of how mHTT protein misfolding and aggregation occur and how this affects cellular function.
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Hemmati, Houman David Rothenberg Ellen V. "Neural stem and progenitor cells in cancer and development /." Diss., Pasadena, Calif. : Caltech, 2006. http://resolver.caltech.edu/CaltechETD:etd-05232006-140457.
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Robins, Sarah. "Neural stem/progenitor cells in the adult mouse hypothalamus." Thesis, University of Sheffield, 2009. http://etheses.whiterose.ac.uk/111/.
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Adult neural stem cells are now widely accepted to exist in the neurogenic regions of the subventricular zone and dentate gyrus; however there is increasing evidence to suggest that neurogenesis may also occur in other brain regions. It has been proposed that one such population of neural stem cells resides in the hypothalamus, more specifically in the ependymal lining of the third ventricle. In this thesis, I tested the hypothesis that stem cells exist in defined regions of the adult mouse hypothalamus. My work confirms the presence of stem/progenitor cells in the adult mouse hypothalamus. Analysis of neural 'stem cell markers', both in vivo and in vitro, suggests the presence of different populations of stem/progenitor cells occupying discrete territories of the ependymal zone. Some markers are common to those found in other adult neural stem cell niches, whilst others are unique to the hypothalamus. I have isolated hypothalamic stem/progenitor cells, and assayed their character and potential for both self-renewal and differentiation using the neurosphere assay. I show that hypothalamic neurospheres can be propagated in culture for extended periods of time, and that they can differentiate into cells of all three neural lineages. I have also determined the precise location of neurosphere-forming cells in the hypothalamus, showing that proliferative capacity is restricted to defined regions. Within these regions, I have also identified separate populations of proliferating cells that vary in their capacity for self-renewal, and correlated this with marker profiles. This data supports previous reports suggesting that tanycytes act as neural stem cells in the hypothalamus. Finally, I have started work investigating the control of hypothalamic stem/progenitor proliferation by fibroblast growth factors. I demonstrate that FGF signalling is necessary for in vitro proliferation. Finally, my studies suggest that endogenous FGFs may regulate hypothalamic stem cell proliferation.
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Marshall, Gregory Paul. "Neurospheres and multipotent astrocytic stem cells neural progenitor cells rather than neural stem cells /." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010047.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 97 pages. Includes Vita. Includes bibliographical references.
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Vroemen, Maurice. "Cellular therapy after spinal cord injury using neural progenitor cells /." [S.l. : s.n.], 2006. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014984014&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Rinaldi, Federica. "Connexin 43 influences lineage commitment of human neural progenitor cells." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556745.
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Gap junctions (GJs) are intercellular channels connecting the cytoplasm of adjacent cells. This type of connection is an efficient way of cellular communications in many tissues including the central nervous system. Connexins are the proteins that constitute mammalian GJs, and Connexin43 (Cx43) is the most abundant isoform expressed in body cells. Cx43 has been detected within immature neural populations, but only in astrocytes in the adult brain and investigations have shown that Cx43 channel and adhesive properties largely influence neuronal differentiation of mouse neural progenitor (NP) cells. To date the role of Cx43 in neuronal differentiation remains unexplored in human systems, hence our study aimed to investigate the Cx43 participation in human NP differentiation. We largely detected Cx43 protein within the immature neural populations showing that protein expression occurred by fibroblast growth factor (FGF _2) stimulation through the ERKlj2 pathway; FGF _2 withdrawal induced NP differentiation and a progressive loss in Cx43 expression. Cx43's role in neuronal differentiation was explored by cloning lentiviral vectors (LV) coding for Cx43 or anti-Cx43 shRNA constructs and the protein knockdown resulted in an increase in neurons and a decrease in astrocytes, suggesting a role for Cx43 in human stem cell differentiation and neuronal fate. GJs mediate intercellular communications of several mouse and human embryonic stem (ES) cell lines; in our investigation we also showed the presence of functional GJ channels in human ES cells, as well as Cx43 protein expression. Manipulation of ES cells was attempted using LVs and results indicated that the CMV promoter in ES cells is largely inactive. In summary I demonstrated the active role of Cx43 in mechanisms that govern neurogenesis and differentiation of neural progenitor cells, furthermore we highlighted the importance of the internal promoter in LV constructs for genetic manipulation of embryonic ES cells.
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Howard-Jones, Rachel Anne. "Oral progenitor cells as cell-based treatment for neural damage." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/52753/.
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Over the past few decades stem cells have been extensively investigated due to their potentially invaluable therapeutic use. Embryonic stem cells (ESCs) have wide-ranging therapeutic applications in tissue repair and regeneration due to their pluripotent properties and their ability to self-renew indefinitely. However, ethical concerns surround their use and hence alternatives are sought. Adult stem cells (ASCs) have been isolated from various adult tissues including the oral mucosa lamina propria (OMLP). This study aims to isolate ASCs from the OMLP, reprogram these cells to induced pluripotent stem cells (iPSCs) and determine the potential for both to differentiate into functional neurons due to the limited regeneration of neurons in the central nervous system. Such investigations into strategies for the treatment of neural damage are invaluable and timely due to current limitations in the availability of human-derived cells for potential autologous or allogeneic tissue repair. OMLP-PCs represent an ideal cell source for use in regenerative medicine given their ease of isolation, proliferative potential, multipotent properties and immunosuppressive activities. Work in this Thesis has now demonstrated that these oral progenitors expressed numerous pluripotency markers and for the first time, that they could be reprogrammed to iPSCs utilising safer, non-integrating plasmids, thus increasing their potential for use in clinical applications. OMLP-iPSCs were positive for a number of pluripotent stem cell markers including SSEA-4, SSEA-5, TRA-1-60, TRA-1-81, Oct-4 and Sox-2. Moreover, their expression of early stage germ layer markers indicated their potential to differentiate into cell types of the mesoderm, endoderm and ectoderm. OMLP-PCs were also demonstrated within this Thesis to differentiate down an early neural lineage as evidenced by the presence of typical neural markers (Nestin, βIII tubulin, MAP-2 and NF-M). The presence of both ligand-gated and voltage-sensitive calcium channels indicated some limited potential functional phenotype. Unfortunately, utilising the same neural differentiation methodology, OMLP-iPSCs were not able to be similarly driven down a neural pathway. None-the-less this data suggests that OMLP-PCs and OMLP-iPSCs may hold great promise for a wide range of regenerative medicine applications
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Premarathne, Susitha. "Role of Deubiquitylating Enzyme USP9X in Neural Progenitor Fate Determination." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/367800.
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During brain development, neural progenitors (NPs) need to balance their self-renewal with differentiation, in order to maintain the NP population while establishing the complex tissue architecture of the brain. NP fate is under the close scrutiny of plethora of fate determination factors, which can be divided into two groups based on their site of origin namely, intrinsic and extrinsic fate determinants. To date, a number of intrinsic factors, such as cell polarity and adhesion, and extrinsic factors including Notch, WNT and mTOR signaling pathways have been shown to regulate NP fate specification. Despite a modest understanding of how individual fate determinant pathways influence NP fate, number of significant and fundamental questions remains to be answered; many of which centre on the integration and regulation of distinct determinant factors. The current study focused on understanding how the posttranslational modification, deubiquitylation, contributes to NP fate determination. Conditional deletion of the deubiquitylating enzyme, Usp9x from mouse NPs results in perinatal lethality and diffused cortical cellular architecture during late embryonic stages signifying its importance in NP fate specification (Stegeman et al., 2013). In light of this previous study, the overarching aim of this project was to identify roles, if any, of Usp9x in neural progenitor fate specification.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Simmons, Ambrosia. "The Role of Polarity Complex Proteins in Neural Progenitor Proliferation." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/552083.
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Biomedical SciencesPh.D.
Cortical malformations arise from defects in any stage of brain development and often result in life-long disability ranging from epilepsy to developmental delay and even perinatal lethality. The neuroepithelium of the emergent cortex lays the foundation on which the future cortex will develop, and as such, neuroepithelial tissue and the neural progenitor cells (NPCs) which comprise it are critical to the proper growth and development of the cortex. Here I demonstrate the significance of neuroepithelial cell polarity determinants in cortical development and how they affect both junctional integrity and the regulation of NPC proliferation leading to a variety of cortical malformations. Until now, the role of basal polarity complex protein Lgl1 in cortical development remained elusive due to perinatal lethality in animal models. To bypass this, we developed a novel conditional knockout mouse model of Lgl1 in the neuroepithelium and show that Lgl1 is essential to the maintenance of neuroepithelial integrity and regulation of NPC proliferation. Loss of Lgl1 results in a displaced ventricular zone with widespread ectopic proliferation resulting in severe periventricular nodular heterotopia (PNH). Furthermore, Lgl1 loss reduces the cell cycle length resulting in hyperproliferation leading to neuronal overproduction. Together, this work identifies a novel genetic cause of PNH. Next, I aimed to characterize the interaction of Lgl1 with other polarity proteins and downstream signaling pathways in cortical development. Apical and basal polarity proteins have demonstrated mutual antagonism in the establishment/maintenance of epithelial polarity; however, little is known about the role of this antagonism on cortical size and structure or the signaling pathways through which it acts. To address these questions we generated multiple genetic mouse models to investigate the opposing roles of basal protein, Lgl1, and either apical proteins Pals1 or Crb2. Concurrent loss of Pals1 and Lgl1 was able to prevent heterotopic nodules and increase proliferation compared to loss of Pals1 alone. However, cortical size was severely diminished due to overriding effects of Pals1 on cell survival that was unmitigated by Lgl1 loss. Remarkably, loss of both Crb2 and Lgl1 restored the cortex and hippocampus to near normal morphology with a profound rescue of cortical size, suggesting their essential antagonism in both cortical and hippocampal development. Importantly, genetic manipulation through reduction of YAP/TAZ expression in the Lgl1 CKO eliminates periventricular nodules and restores cortical thickness to that of WT cortices. This important finding implicates Lgl1 in the regulation of YAP/TAZ in cortical development. Finally, we investigated a possible downstream target of Pals1 in cell survival, BubR1. My work demonstrates that loss of Pals1 reduces BubR1 expression, which is an essential regulator of the mitotic checkpoint and causative gene of the human disorder Mosaic Variegated Aneuploidy. I show that loss of BubR1 results in significant apoptosis across all cell types in the cortex leading to microcephaly. These data provide the first link between cell polarity determinants and mitotic regulation in the cortex and suggests that BubR1 reduction likely contributes to the decreased cell survival following Pals1 loss. Overall these findings implicate impaired polarity complex function in a wide variety of NPC defects resulting in multiple cortical malformations. My work shows that polarity proteins regulate every stage of the NPCs life cycle from cell division and proliferation to cell survival through regulation of mitosis and YAP/TAZ signaling.
Temple University--Theses
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Wang, Jinju. "Co-transplantation of Endothelial Progenitor Cells and Neural Progenitor Cells for Treating Ischemic Stroke in a Mouse Model." Wright State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=wright1469545055.
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Gurok, Ulf. "Gene expression changes in the course of neural progenitor cell differentiation." [S.l.] : [s.n.], 2004. http://www.diss.fu-berlin.de/2005/91/index.html.
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Wallenquist, Ulrika. "Neural Stem and Progenitor Cells as a Tool for Tissue Regeneration." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110095.
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Neural stem and progenitor cells (NSPC) can differentiate to neurons and glial cells. NSPC are easily propagated in vitro and are therefore an attractive tool for tissue regeneration. Traumatic brain injury (TBI) is a common cause for death and disabilities. A fundamental problem following TBI is tissue loss. Animal studies aiming at cell replacement have encountered difficulties in achieving sufficient graft survival and differentiation. To improve outcome of grafted cells after experimental TBI (controlled cortical impact, CCI) in mice, we compared two transplantation settings. NSPC were transplanted either directly upon CCI to the injured parenchyma, or one week after injury to the contralateral ventricle. Enhanced survival of transplanted cells and differentiation were seen when cells were deposited in the ventricle. To further enhance cell survival, efforts were made to reduce the inflammatory response to TBI by administration of ibuprofen to mice that had been subjected to CCI. Inflammation was reduced, as monitored by a decrease in inflammatory markers. Cell survival as well as differentiation to early neuroblasts seemed to be improved. To device a 3D system for future transplantation studies, NSPC from different ages were cultured in a hydrogel consisting of hyaluronan and collagen. Cells survived and proliferated in this culturing condition and the greatest neuronal differentiating ability was seen in cells from the newborn mouse brain. NSPC were also used in a model of peripheral nervous system injury, and xeno-transplanted to rats where the dorsal root ganglion had been removed. Cells survived and differentiated to neurons and glia, furthermore demonstrating their usefulness as a tool for tissue regeneration.
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Toeg, Hadi D. "Role of connexin 30 in directing adult neural progenitor cell fate." Thesis, University of Ottawa (Canada), 2009. http://hdl.handle.net/10393/27806.
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This thesis tested the hypothesis that the gap junction protein connexin 30 (Cx30) plays a role in regulating adult neural progenitor cell (NPC) fate. Cx30, previously shown to be expressed by postnatal astrocytes, was localized, for the first time, to adult NPCs specifically to a subset of multipotential nestin+/glial fibrillary acidic protein + (GFAP)+ NPCs in the subventricular zone (SVZ) of adult mice. When bromodeoxyuridine (BrdU) labelling was performed in Cx30 (-/-) mice, the transition of early NPCs to a neuronal lineage was reduced. Increased BrdU cell number in the rostral migratory stream and the olfactory bulb was observed in Cx30(-/-) mice which suggested enhanced survival or migration of these immature progeny Enhanced neuronal specification, induced by co-culture with NPCs and astrocytes, was blocked by pharmacological inhibition of gap junction intercellular communication. Together, these results suggest a role for Cx30 in regulating adult NPC fate by promoting neurogenesis through direct cell-cell communication.
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Hertwig, Falk [Verfasser]. "Development of brain tumors from neural stem, progenitor cells / Falk Hertwig." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1027308503/34.
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Nakano, Ichiro. "Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation." Kyoto University, 2008. http://hdl.handle.net/2433/135920.
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Jones, Erin Boote. "Effects of substrate and co-culture on neural progenitor cell differentiation." [Ames, Iowa : Iowa State University], 2008.
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Stewart, Iain. "Characterisation of adult neural stem/progenitor cells in the murine hypothalamus." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/5415/.
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Recent evidence has shown that adult neurogenesis is sustained in the hypothalamus, a region of the ventral diencephalon that is the central regulator of homeostasis. While studies support a role for adult neurogenesis in energy balance, as yet, the identity of the neural stem/progenitor cell niche remains contested. Tanycyte cells, a unique population to the hypothalamus, present a possible candidate due to their diverse roles, radial-glial like morphology and position adjacent to the 3rd ventricle. Here, I provide in-vivo, in-vitro and ex-vivo data that together support alpha-tanycytes as a neural stem/progenitor cell population. My studies show that the embryonic neural stem/progenitor characteristics of radial glia, including expression profile, a basal process and an apical primary cilium, are maintained in alpha-tanycytes during adulthood. In addition, alphatanycytes are multipotent in-vivo and contribute to the other tanycyte populations, suggesting a lineage relationship of cells within the hypothalamic ventricular zone. A neurosphere assay adds further validity to the idea that there is heterogeneity in progenitor status within tanycyte subpopulations. Furthermore, alpha-tanycytes are responsive to Fgf-signalling in-vivo, a crucial regulator of proliferation and differentiation during embryogenesis, as well as being required for neurosphere formation. In order to further interrogate alpha-tanycytes, I developed and optimised an organotypic slice culture protocol, a technique that has not yet been used to study hypothalamic neural stem/progenitor cell dynamics. This ex-vivo technique provides a number of advantages including efficiency, low-cost, and amenability to manipulation, while maintaining large parts of the niche. Exogenous addition of pharmacological agonists and inhibitors reveals that alpha-tanycytes undergo Fgf-dependent proliferation in response to physiological stimulation, and implicates a role for the hypothalamic niche in the homeostatic control of stress. Together, these studies characterise the component cells of the adult hypothalamic neural stem/progenitor cell niche, providing a framework for future research to further explore the heterogeneity and physiological significance of alpha-tanycytes.
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Salvalai, Maria Elisa. "Trisomic neural progenitor cells as novel pharmacological targets in Down Syndrome." Doctoral thesis, Università del Piemonte Orientale, 2020. http://hdl.handle.net/11579/114793.
Full textAbstract:
Down syndrome (DS) is the main genetic cause of intellectual disability. Decreased proliferation of Neural Progenitor Cells (NPC), widespread neurogenesis impairment and increased astrogliogenesis are considered among the major determinants of brain atrophy and intellectual disability in DS individuals. The best characterized and studied animal model for DS is the Ts65Dn mouse line which recapitulates several features of the human pathology, including cognitive impairment. In the recent years studies suggested that perinatal pharmacotherapies targeting NPC alterations may represent potential interventions in DS. However, at present, no pharmacotherapies are suitable for clinical application.
Thus, the need to identify new and safe pharmacotherapies to improve intellectual disability in DS patients. Based on these data, our overall goal was to unravel novel mechanisms underlying We generated and phenotypically characterized NPC from Ts65Dn and euploid pups (P1, 2). We then targeted NPC alterations using at first a phenotypic-based approach that identified 30
FDA/EMA approved drugs able to correct trisomic NPC defective proliferation. Importantly, among the potential hits we identified the immunosuppressant cyclosporine A (CSA). We showed that a neonatal treatment with CSA (P3-P15) corrected the whole triad of defects of DS brain. In parallel, we used a target based approach, exploiting the effect of an agonist of the tropomyosin
receptor kinase B, 7,8-DHF, and corn oil on neurogenesis in vitro and in vivo, also evaluating the cognitive performances.
In the last part of this thesis we identified new molecular mechanisms altered in trisomic NPC in response to the key astrocytic signal thrombospondin-1. Taken together these data showed that trisomic NPC dysfunctions are pharmacologically relevant
targets in DS.
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Meyer, Anne K. "Intracellular signaling cascades in the dopaminergic specification of fetal mesencephalic neural progenitor cells." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1245401735166-83393.
Full textAbstract:
Neural stem (progenitor) cells (NPCs) from fetal tissue are an ideal transplantable cell source. They divide rapidly, are able to generate cells of all three neural lineages and do not divide uncontrolled once transplanted into a host organism. To obtain large quantities of cells for transplantation strategies and to eliminate primary cell contaminations, long periods of in vitro cultivation are necessary. Mouse NPCs are a crucial tool for further investigations of neural stem cells because they make the employment of transgenic animals in vivo and cells in vitro possible. So far only short-term expanded fetal mouse NPCs have been shown to generate dopaminergic neurons and it is not clear whether this was due to differentiation or a result of increased survival of primary dopaminergic neurons. The aims of the thesis were to characterize mouse fetal NPCs, to establish the long-term expansion of fetal mouse NPCs and the generation of dopaminergic neurons in long-term expanded fetal mouse NPCs, to investigate the signaling mechanisms involved in the differentiation of mouse fetal NPCs towards the dopaminergic phenotype and to compare short and long-term expanded NPCs. Long-term expanded fetal mesencephalic NPCs could be grown under suspension and adherent culture conditions and showed self- renewing capacity as well as markers typical for NPCs. They could be differentiated into the three major cell types of the nervous system, but suspension NPCs had a larger potential to generate neurons than adherently grown NPCs. Signaling cascades involved in this process were p38 and Erk1/2 mediated. Long-term expanded NPCs did not have the potential to generate neuronal sub-types. Importantly, they did not generate dopaminergic neurons. Mouse fetal NPCs from three different developmental stages (E10, E12, and E14) were employed but were not able to differentiate into dopaminergic neurons using factors known to stimulate in vitro dopaminergic specification. When cultivated in vitro for short periods, fetal mesencephalic NPCs were able to generate dopaminergic neurons. By eliminating all primary Th- positive neurons, FACS-sorting of NPCs proved a de novo generation of dopaminergic neurons, because after cultivation and differentiation of Th- depleted cell solutions dopaminergic neurons were present in the culture. However, these newly generated neurons failed to incorporate BrdU, making a generation without cell division from precursors probable. The precursor population of short cultures differed from long-term expanded cultures suggesting an ‘aging’ effect of in vitro conditions. IL-1 was a potent inducer of the dopaminergic neuronal phenotype in short-term expanded in vitro cultures and was expressed in vitro as well as in vivo at E14. Several important conclusions concerning fetal mouse stem cell behavior could be drawn from the results of this work: Firstly, the results showed for the first time that in fetal mouse mesencephalic NPCs dopaminergic neurons differentiate from precursors without cell division, therefore consuming those progenitors. Therein fetal mouse NPCs differ significantly from rat and human NPCs or respond differently to the same in vitro conditions that need to be optimized for fetal mouse NPCs. Secondly, less committed precursors find appropriate conditions to proliferate but not to generate the more committed DA precursors that are able to generate dopaminergic neurons. The hallmarks of stem cells, self-renewal and multipotentiality, seem to be part of a delicate balance, that, when unsettled, goes in favor of one side without the possibility of returning to the previous status. Further research should focus on two coherent issues: the isolation of more pure populations of progenitors and the more precise characterization of progenitor populations to find out which in vitro conditions need to be provided to keep the balance between proliferation and differentiation potential. The knowledge gained about stem cells this way would help establish cell sources for transplantation strategiesStammzellen sind ein wichtiges Werkzeug für regenerative Therapien im Bereich der neurodegenerativen Erkrankungen wie der Parkinson’schen Erkrankung. Ein besonderer Vorteil von Stammzellen gegenüber dem bereits zur Transplantation verwendeten Primärgewebe, ist ihre Fähigkeit zur fortlaufenden Zellteilung, so dass ausreichende Mengen zur Transplantation zur Verfügung stehen. Der Vorteil von fetalen neuralen Stammzellen (fNSZ) ist ihre genomische Stabilität, die dazu führt, dass bei Transplantationen keine Tumore entstehen. Dennoch ist der Großteil ihrer Eigenschaften und Potentiale noch unbekannt und die optimalen Wachstumsbedingungen für eine lange in vitro Kultur und optimale Differenzierung in dopaminerge Neuronen müssen erforscht werden, um bessere Transplantate herzustellen. Insbesondere Stammzellen der Maus sind für die Forschung von immenser Wichtigkeit, da sie die Arbeit mit transgenen Tieren ermöglichen. Die Zielsetzungen dieser Arbeit waren die Charakterisierung der fNSZ der Maus, die Langzeitexpansion und die anschließende Differenzierung in dopaminerge Neurone. Die Signalkaskaden der frühen Differenzierung und die Unterschiede von kurz- und langzeitkultivierten Stammzellen wurden untersucht. Es konnte gezeigt werden, dass fNSZ der Maus nach Langzeitkultivierung in alle Zelltypen des zentralen Nervensystems, also Neuronen und Glia differenzieren und die dabei aktivierten Signalkaskaden p38 und Erk1/2 vermittelt sind. Das Differenzierungspotential zu neuronalen Subtypen (also auch zu dopaminergen Nervenzellen) verloren diese fetalen Stammzellen unter Kulturbedingungen schnell. Das steht im Gegensatz zu fetalen Stammzellen aus Ratte oder dem Menschen, die auch nach langer Kultivierung ihr dopaminerge Potential erhalten. Nur nach Kurzzeitkultivierung waren dopaminerge Neurone nachzuweisen, die jedoch nicht durch Zellteilung aus Vorläuferzellen hervorgegangen waren. Die Eliminierung aller primären Neurone aus der Mittelhirnisolation durch FACS-sorting von Th-Gfp transgenen Mäusen bewies die de novo Generation der dopaminergen Neurone aus Vorläuferzellen ohne Zellteilung während der Kultivierung der Stammzellen. Diese Ergebnisse zeigten, dass in fetalen mesenzephalen NSZ der Maus dopaminerge Neurone von spezialisierten Vorläuferzellen differenzieren, wodurch diese der Kultur verloren gehen. Weniger spezialisierte Vorläuferzellen finden Bedingungen, die ihre Kultivierung ermöglichen, sind aber nicht in der Lage, spezifischere Vorläuferzellen zu bilden. Die Markenzeichen von Stammzellen, Selbsterneuerung (durch Zellteilung) und das Potential, die Zelltypen des Nervensystems zu generieren, scheinen fein balancierte Zustände zu sein, die bei einer Störung nicht wiederherzustellen sind. Die Ergebnisse dieses Projektes sind von großer Bedeutung für die Forschung zur Zellersatztherapie der Parkinson’schen Erkrankung, deren ultimatives Ziel es ist, eine sichere und verlässlich expandierbare Zellquelle zu etablieren, die fähig ist, in dopaminerge Neurone zu differenzieren. Solche Stammzellen würden Bemühungen um Transplantationsstrategien für neurodegenerative Erkrankungen unterstützen und vorantreiben
27
Meyer, Anne K. "Intracellular signaling cascades in the dopaminergic specification of fetal mesencephalic neural progenitor cells." Doctoral thesis, Technische Universität Dresden, 2008. https://tud.qucosa.de/id/qucosa%3A23891.
Full textAbstract:
Neural stem (progenitor) cells (NPCs) from fetal tissue are an ideal transplantable cell source. They divide rapidly, are able to generate cells of all three neural lineages and do not divide uncontrolled once transplanted into a host organism. To obtain large quantities of cells for transplantation strategies and to eliminate primary cell contaminations, long periods of in vitro cultivation are necessary. Mouse NPCs are a crucial tool for further investigations of neural stem cells because they make the employment of transgenic animals in vivo and cells in vitro possible. So far only short-term expanded fetal mouse NPCs have been shown to generate dopaminergic neurons and it is not clear whether this was due to differentiation or a result of increased survival of primary dopaminergic neurons. The aims of the thesis were to characterize mouse fetal NPCs, to establish the long-term expansion of fetal mouse NPCs and the generation of dopaminergic neurons in long-term expanded fetal mouse NPCs, to investigate the signaling mechanisms involved in the differentiation of mouse fetal NPCs towards the dopaminergic phenotype and to compare short and long-term expanded NPCs. Long-term expanded fetal mesencephalic NPCs could be grown under suspension and adherent culture conditions and showed self- renewing capacity as well as markers typical for NPCs. They could be differentiated into the three major cell types of the nervous system, but suspension NPCs had a larger potential to generate neurons than adherently grown NPCs. Signaling cascades involved in this process were p38 and Erk1/2 mediated. Long-term expanded NPCs did not have the potential to generate neuronal sub-types. Importantly, they did not generate dopaminergic neurons. Mouse fetal NPCs from three different developmental stages (E10, E12, and E14) were employed but were not able to differentiate into dopaminergic neurons using factors known to stimulate in vitro dopaminergic specification. When cultivated in vitro for short periods, fetal mesencephalic NPCs were able to generate dopaminergic neurons. By eliminating all primary Th- positive neurons, FACS-sorting of NPCs proved a de novo generation of dopaminergic neurons, because after cultivation and differentiation of Th- depleted cell solutions dopaminergic neurons were present in the culture. However, these newly generated neurons failed to incorporate BrdU, making a generation without cell division from precursors probable. The precursor population of short cultures differed from long-term expanded cultures suggesting an ‘aging’ effect of in vitro conditions. IL-1 was a potent inducer of the dopaminergic neuronal phenotype in short-term expanded in vitro cultures and was expressed in vitro as well as in vivo at E14. Several important conclusions concerning fetal mouse stem cell behavior could be drawn from the results of this work: Firstly, the results showed for the first time that in fetal mouse mesencephalic NPCs dopaminergic neurons differentiate from precursors without cell division, therefore consuming those progenitors. Therein fetal mouse NPCs differ significantly from rat and human NPCs or respond differently to the same in vitro conditions that need to be optimized for fetal mouse NPCs. Secondly, less committed precursors find appropriate conditions to proliferate but not to generate the more committed DA precursors that are able to generate dopaminergic neurons. The hallmarks of stem cells, self-renewal and multipotentiality, seem to be part of a delicate balance, that, when unsettled, goes in favor of one side without the possibility of returning to the previous status. Further research should focus on two coherent issues: the isolation of more pure populations of progenitors and the more precise characterization of progenitor populations to find out which in vitro conditions need to be provided to keep the balance between proliferation and differentiation potential. The knowledge gained about stem cells this way would help establish cell sources for transplantation strategies.Stammzellen sind ein wichtiges Werkzeug für regenerative Therapien im Bereich der neurodegenerativen Erkrankungen wie der Parkinson’schen Erkrankung. Ein besonderer Vorteil von Stammzellen gegenüber dem bereits zur Transplantation verwendeten Primärgewebe, ist ihre Fähigkeit zur fortlaufenden Zellteilung, so dass ausreichende Mengen zur Transplantation zur Verfügung stehen. Der Vorteil von fetalen neuralen Stammzellen (fNSZ) ist ihre genomische Stabilität, die dazu führt, dass bei Transplantationen keine Tumore entstehen. Dennoch ist der Großteil ihrer Eigenschaften und Potentiale noch unbekannt und die optimalen Wachstumsbedingungen für eine lange in vitro Kultur und optimale Differenzierung in dopaminerge Neuronen müssen erforscht werden, um bessere Transplantate herzustellen. Insbesondere Stammzellen der Maus sind für die Forschung von immenser Wichtigkeit, da sie die Arbeit mit transgenen Tieren ermöglichen. Die Zielsetzungen dieser Arbeit waren die Charakterisierung der fNSZ der Maus, die Langzeitexpansion und die anschließende Differenzierung in dopaminerge Neurone. Die Signalkaskaden der frühen Differenzierung und die Unterschiede von kurz- und langzeitkultivierten Stammzellen wurden untersucht. Es konnte gezeigt werden, dass fNSZ der Maus nach Langzeitkultivierung in alle Zelltypen des zentralen Nervensystems, also Neuronen und Glia differenzieren und die dabei aktivierten Signalkaskaden p38 und Erk1/2 vermittelt sind. Das Differenzierungspotential zu neuronalen Subtypen (also auch zu dopaminergen Nervenzellen) verloren diese fetalen Stammzellen unter Kulturbedingungen schnell. Das steht im Gegensatz zu fetalen Stammzellen aus Ratte oder dem Menschen, die auch nach langer Kultivierung ihr dopaminerge Potential erhalten. Nur nach Kurzzeitkultivierung waren dopaminerge Neurone nachzuweisen, die jedoch nicht durch Zellteilung aus Vorläuferzellen hervorgegangen waren. Die Eliminierung aller primären Neurone aus der Mittelhirnisolation durch FACS-sorting von Th-Gfp transgenen Mäusen bewies die de novo Generation der dopaminergen Neurone aus Vorläuferzellen ohne Zellteilung während der Kultivierung der Stammzellen. Diese Ergebnisse zeigten, dass in fetalen mesenzephalen NSZ der Maus dopaminerge Neurone von spezialisierten Vorläuferzellen differenzieren, wodurch diese der Kultur verloren gehen. Weniger spezialisierte Vorläuferzellen finden Bedingungen, die ihre Kultivierung ermöglichen, sind aber nicht in der Lage, spezifischere Vorläuferzellen zu bilden. Die Markenzeichen von Stammzellen, Selbsterneuerung (durch Zellteilung) und das Potential, die Zelltypen des Nervensystems zu generieren, scheinen fein balancierte Zustände zu sein, die bei einer Störung nicht wiederherzustellen sind. Die Ergebnisse dieses Projektes sind von großer Bedeutung für die Forschung zur Zellersatztherapie der Parkinson’schen Erkrankung, deren ultimatives Ziel es ist, eine sichere und verlässlich expandierbare Zellquelle zu etablieren, die fähig ist, in dopaminerge Neurone zu differenzieren. Solche Stammzellen würden Bemühungen um Transplantationsstrategien für neurodegenerative Erkrankungen unterstützen und vorantreiben.
28
Ochi, Shohei. "Oscillatory expression of Hes1 regulates cell proliferation and neuronal differentiation in the embryonic brain." Kyoto University, 2020. http://hdl.handle.net/2433/253484.
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Noisa, Parinya. "Characterization of neural progenitor/stem cells derived from human embryonic stem cells." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/5712.
Full textAbstract:
Human embryonic stem cells (hESCs) are able to proliferate indefinitely without losing their ability to differentiate into multiple cell types of all three germ layers. Due to these fascinating properties, hESCs have promise as a robust cell source for regenerative medicine and as an in vitro model for the study of human development. In my PhD study, I have investigated the neural differentiation process of hESCs using our established protocol, identified characteristics associated with each stage of the differentiation and explored possible signalling pathways underlying these dynamic changes. It was found that neural differentiation of hESCs could be divided into 5 stages according to their morphology, marker expression and differentiation potencies: hESCs, neural initiation, neural epithelium/rosette, neuronal progenitor cells and neural progenitor/stem cells (NPSCs) and 4 of these stages have been studied in more detail. At the neural initiation, hESCs firstly lose TRA-1-81 expression but retain SSEA4 expression. This transient cell population shows several similar properties to the primitive ectoderm. After neural-tube like structure/neural rosette formation, neural progenitor cells appear as typical bipolar structures and exhibit several properties of radial glial cells, including gene expression and pro-neuronal differentiation. The neural progenitor cells are able to grow in culture for a long time in the presence of growth factors bFGF and EGF. However, they gradually lose their bipolar morphology to triangular cell type and become pro-glial upon further differentiation. In addition, the state of neural progenitor and stem cells can be distinguished by their differential response to canonical Notch effector, C protein-binding factor 1. It was also found that delta like1 homolog (DLK-1) is temporally upregulated upon initial neural differentiation, but becomes undetectable after the neural progenitor stage. Overexpression of DLK-1 in NPSCs enhances neuronal differentiation in the presence of serum by blocking BMP and Notch pathways. These results show that neural differentiation of hESCs is a dynamic process in which cells go through sequential changes, and the events are reminiscent of the in vivo neurodevelopment process. Moreover, I have characterized stably transfected nestin-GFP reporter hESC lines and found that the cell lines maintained the features of hESCs and the expression of GFP is restricted to the neural lineage after differentiation. Therefore, these reporter lines will be useful for the study of factors that regulate neural differentiation and for the enrichment of neural progenitors from other lineages. Taken together, this study has demonstrated that hESCs are a good in vitro model to study the mechanisms and pathways that are involved in neural differentiation. The availability of hESCs allows us to explore previously inaccessible processes that occur during human embryogenesis, such as gastrulation and neurogenesis.
30
Larsson, Jimmy. "Neural stem and progenitor cells cellular responses to known and novel factors /." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110722.
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Li, Yue, and 李越. "Caveolin-1 is a negative regulator of neuronal differentiation of neural progenitor cells in vitro and in vivo." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46918863.
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Knight, Julia. "Roles of Fas in Neural Progenitor Cell Differentiation, Survival, and Immune-Cell Interactions." ScholarWorks @ UVM, 2011. http://scholarworks.uvm.edu/graddis/124.
Full textAbstract:
Multiple sclerosis (MS) is a leading cause of neurological disability in young adults. Although current treatments can reduce symptomology and relapse rate, they are unable to prevent the chronic neurodegeneration that occurs at later stages. MS pathology is mediated by complex interactions between invading immune cells, neurons, glia, and endogenous stores of neural progenitor cells (NPCs). Factors critical to NPC/immune cell communication as well as the survival, differentiation, and proliferation of NPCs are not well defined. Elucidation of these factors will allow for the advancement of NPC transplantation therapies as well as the identification of novel pharmacological targets. Fas – a member of the tumor necrosis superfamily of death receptors – has diverse, cell-specific functions and is a major modulator of autoregulation within the immune system. Although Fas is expressed by NPCs, its exact role in this cell type was previously unknown. To contribute to this body of knowledge, the experiments in this dissertation examined the role of the Fas receptor (Fas) and Fas ligand (FasL) in NPC survival, differentiation, and T-cell cross-talk in vitro and in vivo in experimental autoimmune encephalomyelitis (EAE; a well-established animal model of MS). Activation of Fas via FasL increased NPC survival by decreasing apoptosis (as opposed to increasing proliferation) in vitro. This decreased apoptosis correlates with upregulation of the inhibitor of apoptosis protein (IAP) Birc3. Further investigation into the importance of Fas in NPCs was accomplished by comparing wild-type and Fas-deficient (lpr) NPCs. Lpr NPCs exhibited decreased apoptosis, decreased proliferation, and increased differentiation to oligoprogenitor and neuronal lineages. These studies suggest the Fas system plays multifaceted roles in NPCs and that its exact functions are dependent on both functional Fas expression and presence or absence of FasL. To determine the role of Fas/FasL in neuroimmune cross-talk, co-cultures of wild-type or lpr NPCs with different T-cell subtypes (Th1, Th2, and Th17 cells) were performed. Th1 cells were the only subtype capable of inducing NPC apoptosis. Th1-mediated death was dose-dependent and was not mediated via Fas. On the other hand, NPCs were able to induce significant apoptosis in pro-inflammatory Th1 and Th17 cells without affecting anti-inflammatory Th2 cells. NPC-induced Th17 cell death was mediated via Fas. These data suggest NPCs can specifically target pro-inflammatory T-cells and can promote neuroprotection by inducing death of these proencephalogenic cells. Finally, intravenous injection of wild-type or lpr NPCs into EAE mice reduced clinical symptoms and CNS immune infiltrate to the same extent. Few NPCs enter the CNS, where they remain undifferentiated. This suggests the main mechanism through which NPCs produce beneficial results in EAE is via peripheral immunoregulation, which is not dependent on Fas expression. Overall, this dissertation elucidates the Fas system as an important modulator of NPC cell-fate and immunoregulatory capacity.
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Rennick, Stephen D. "Mammalian ISWI gene knockdown modulates growth and differentiation properties of neural progenitor cells." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27606.
Full textAbstract:
Epigenetic modifications during cellular differentiation are critical for establishing the expression of tissue specific genes characterizing particular cell types. There are two groups of chromatin modifying enzymes that regulate these processes, the ATP-dependent complexes, and the histone modifying complexes. In ATP-dependent remodelling complexes, the imitation switch (ISWI) group has been studied extensively in the past. ISWI proteins were initially discovered in Drosophila and mammals contain two orthologs called SNF2H and SNF2L. Past experiments demonstrated that these remodelers have distinct roles in cellular differentiation and proliferation SNF2H expression is greatest in proliferating neuroprogenitor populations, whereas SNF2L predominates in mature neurons. Additionally, SNF2H null mice are periimplantation lethal due to defective cellular proliferation. Other studies showed that neuronal cell cultures ectopically expressing increased levels of SNF2L display a dramatic increase in neurite extension and spontaneous differentiation. These findings point to requirements for SNF2L during neuronal differentiation but the distinct manner in which ISWI proteins oversee this process remains unknown. To elucidate the role of ISWI proteins in the regulation of neuronal proliferation and differentiation we used shRNA transfection to stably knockdown the genes of interest in established neuronal cell lines. Concurrently, we examined the growth and differentiation properties of primary neuronal cultures derived from mice functionally ablated for Snf2l. Results in neuroblastoma cultures show that upon Snf2l knockdown proliferation is maintained in 30% of the population under differentiation conditions at 4 days of differentiation. In contrast, Snf2H knockdown cells proliferate normally but undergo extensive apoptosis when induced to differentiate. Aberrant cell replication was also observed in E14.5 and E12.5 neurosphere cultures and resulted in a 2-fold decrease in the number of neurons generated and a 4-fold reduction in astrocyte production at 4 days of differentiation. Moreover, both astrocytes and neurons expressing differentiation markers had reduced neurite extensions and branching patterns suggesting a distinct developmental delay. Taken together these studies define distinct roles for ISWI in growth and differentiation of CNS cells.
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Faijerson, Jonas. "Neural stem/progenitor cells in the post-ischemic environment : proliferation, differentiation and neuroprotection /." Göteborg : Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, 2007. http://hdl.handle.net/2077/4516.
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Hermann, Robert [Verfasser], and Ana [Akademischer Betreuer] Martin-Villalba. "Regulation of Neural Progenitor Proliferation by ANKHD1 / Robert Hermann ; Betreuer: Ana Martin-Villalba." Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1177811464/34.
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Huber, Christophe [Verfasser], and Ludwig [Akademischer Betreuer] Aigner. "Inhibition of leukotriene receptors boosts neural progenitor proliferation / Christophe Huber. Betreuer: Ludwig Aigner." Regensburg : Universitätsbibliothek Regensburg, 2013. http://d-nb.info/103155873X/34.
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Bithell, Angela. "Cellular and molecular studies on neural progenitor cells in the developing rat forebrain." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271827.
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Iacobucci, Simona. "Function of the histone demethylase PHF8 in neural progenitor cells and glial differentiation." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673438.
Full textAbstract:
Taking into consideration the current knowledge about the subjects treated, several goals were proposed for this PhD thesis in order to further understand PHF8 function in both astrocytes and neural stem cells biology. To do that, we determined the following objectives:
1. To investigate the role of PHF8 histone demethylase during astrocytes differentiation.
• Analyse the PHF8-mediated transcriptional profile in astrocytes.
• Determine the chromatin bound regions of PHF8 in astrocytes.
• Elucidate astrocytes phenotype upon PHF8 depletion.
• Examine astrocytic PHF8 function during synaptogenesis.
• Determine the molecular mechanism responsible for the PHF8- associated phenotype in astrocytes.
2. To elucidate the function of PHF8 in neural stem cells.
• Examine neural stem cells phenotype upon PHF8 depletion.
• Determine the PHF8-mediated transcriptional profile in neural stem cells.
• Analyse the metabolic impact of PHF8 depletion.
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CVIJETIC, SUZANA. "Neural Progenitor Cell-astroglia cross-talk: involvement of the NF-kB p50 subunit." Doctoral thesis, Università del Piemonte Orientale, 2016. http://hdl.handle.net/11579/115177.
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Patel, Nirmal Praful School of Medicine UNSW. "Olfactory progenitor cell transplantation into the mammalian inner ear." Awarded by:University of New South Wales. School of Medicine, 2006. http://handle.unsw.edu.au/1959.4/26180.
Full textAbstract:
A practical consideration in the development of cellular therapy technology for the inner ear is the development of an in vitro model for assessing the optimal conditions for successful application of cells. The first part of this thesis describes the adaptation of the cochleovestibular structure harvested from P1 mouse pups for analysis of factors critical for the optimal implantation of stem cells in the inner ear. Results of these studies establish that the c17.2 neural stem cell line can be introduced into the cochleovestibular structure in vitro. Using this model, c17.2 cells demonstrated survival predominantly within the vestibule and basal spiral ganglion regions. Furthermore, the addition of the ototoxin, cisplatin and the neurotrophin, Brain Derived Neurotrophic Growth Factor (BDNF) enhanced the survival and migration/dispersion of c17.2 cells within the cochleovestibular explant. The second part of this thesis examines the hypothesis that olfactory neurosphere (ONS) and progenitor cells harvested from the olfactory epithelium represent a viable source of graft material for potential therapeutic applications in the inner ear. Olfactory epithelium represents a unique source of pluripotent cells that may serve as either homografts or autografts. The feasibility of ONSs to survive and integrate into a mammalian cochlea in vivo was assessed. The ONSs were isolated as a crude fraction from the olfactory epithelium of P1 to P3 day old swiss webster mouse pups, ubiquitously expressing the Green Fluorescent Protein (GFP) marker. The ONSs were microinjected into the cochleae of adult CD1 male mice. Four weeks following their implantation, ONS cells expressing the GFP marker and stained by Nestin were identified in all areas of the cochlea and vestibule, including the spiral ganglion. Robust survival and growth of the implanted ONS and ONS derived cells in the cochlea also included the development of ???tumor-like??? clusters, a phenomenon not observed in control animals implanted with c17.2 neural stem cells. Collectively, the results of this thesis illustrate the potential of olfactory neurosphere and progenitor cells to survive in the inner ear and expose a potential harmful effect of their transplantation.
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Chwastek, Damian. "Elucidating the Contribution of Stroke-Induced Changes to Neural Stem and Progenitor Cells Associated with a Neuronal Fate." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/41839.
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Following stroke there is a robust increase in the proliferation of neural stem and progenitor cells (NSPCs) that ectopically migrate from the subventricular zone (SVZ) to surround the site of damage induced by stroke (infarct). Previous in vivo studies by our lab and others have shown that a majority of migrating NSPCs when labelled prior to stroke become astrocytes surrounding the infarct. In contrast, our lab has shown that the majority of NSPCs when labelled after stroke become neurons surrounding the infarct. This thesis aims to elucidate the contributions of intrinsic changes that can alter the temporal fate of the NSPCs. The NSPCs were fate mapped in this study using the nestin-CreERT2 mouse model and strokes were induced using the photothrombosis model within the cortex. In alignment with our previous findings, fate-mapping the NSPCs using a single injection of tamoxifen treatment revealed a temporal-specific switch in neuronal fate when NSPCs were labeled at timepoints greater than 7 days following stroke. Single cell RNA sequencing and histological analysis identified significant differences in the proportion of populations of NSPCs and their progeny labeled at the SVZ in the absence or presence of a stroke. NSPCs labelled after stroke were comprised of a reduced proportion of quiescent neural stem cells alongside an accompanied increase in doublecortin-expressing neuroblasts. The RNA transcriptional profile of the NSPCs labelled also revealed NSPCs and their progeny labeled after stroke had an overall enrichment for a neuronal transcription profile in all of the labeled cells with a reduction in astrocytic gene expression in quiescent and activated neural stem cells. Furthermore, we highlight the presence of perturbed transcriptional dynamics of neuronal genes, such as doublecortin following stroke. Altogether, our study reveals following a stroke there is a sustained intrinsic regulated neuronal-fated response in the NSPCs that reside in the SVZ that may not be exclusive from extrinsic regulation. This work raises the challenge to learn how to harness the potential of this response to improve recovery following stroke through examining their contributions to recovery.
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Ghazale, Hussein. "Human and mouse spinal cord : a territory of diverse neural stem/progenitor cells, identification and functionality." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT012/document.
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Au cours des 10 dernières années, le laboratoire de JP Hugnot s’est concentré sur les différents pools de progéniteurs et de cellules souches trouvés dans la moelle épinière adulte, chez l’homme comme chez la souris. Ceci est important pour mener ce type de recherche car la moelle épinière est affectée par plusieurs maladies neurodégénératives telles que la sclérose latérale amyotrophique (SLA) et des lésions traumatiques pour lesquelles il n'existe pas de traitement curatif. Chez des animaux comme le poisson zèbre, la moelle épinière peut se régénérer après une lésion en raison de l'activation de progéniteurs / cellules souches endogènes. Ainsi, en recherchant la présence et les propriétés de telles cellules chez les mammifères, en particulier les humains, on pourrait exploiter ces cellules pour la régénération, y compris les neurones. Nous avons procédé au profilage de l'ARN pour comparer la niche de cellules souches humaine et de souris et la niche de cellules souches de souris de la moelle épinière lésée ou non lésée. Cette niche est particulièrement intéressante dans la mesure où, chez les anamniotes, les cellules de l'épendymoglie radiale situées dans cette région sont multipotentes et peuvent générer de nouveaux motoneurones après une lésion. et des cellules similaires, mais non identiques, sont présentes chez la souris. Chez les mammifères, après la lésion, ces cellules de niche prolifèrent et migrent activement pour générer principalement des cellules astrocytaires et peu d'oligodendrocytes qui participent à la cicatrice gliale et à la régénération en fournissant un facteur neurotrophique tel que le CNTF, le HGF et l'IGF-1. Cette niche contient au moins 5 types de cellules et un nouveau type de cellules dorsales exprimant les facteurs de transcription Msx1 et Id4 a été identifié. Ces résultats indiquent que la niche de la moelle épinière adulte chez la Souris et chez l'homme est une mosaïque de cellules ayant différentes origines développementales et conservant des niveaux élevés de gènes de développement neural. Les interactions gliales-neuronales qui soutiennent et maintiennent les neurones intacts peuvent influer sur les maladies neurodégénératives. L'une de ces cellules gliales est l'oligodendrocyte satellite ou cellules satellites périneuronales (PNC). Les PNC sont étroitement associés au soma de gros neurones et largement répandus dans la substance grise du cortex et de la moelle épinière. Cependant, les propriétés cellulaires et les rôles fonctionnels de ces oligodendrocytes non myélinisants n'ont pas encore été découverts. Dans cette étude, les cellules positives à la nestine-GFP sont associées à des neurones immunocolorés pour l'antigène nucléaire neuronal dans le cortex et la moelle épinière. Nous avons identifié les PNC comme étant des cellules positives pour la CNPase qui ne sont ni des cellules progénitrices d'oligodendrocytes (PDGFRa) ni des oligodendrocytes myélinisants (MBP). Ces données suggèrent que les PNC pourraient affecter la survie neuronale ainsi que le processus de myélinisation dans des conditions de démyélinisation. En outre, il pourrait être impliqué dans des maladies neurodégénératives telles que la sclérose en plaques et la sclérose latérale amyotrophique en raison de leur interaction avec les motoneuronesOver the last 10 years, JP Hugnot’s lab has been focusing on the different pools of progenitors and stem cells found in the adult spinal cord both in human and mouse. This is important to conduct this kind of research as the spinal cord is affected by several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and traumatic lesions for which there is no cure. In anamniotes such as Zebrafish, the spinal cord can regenerate after lesion due to endogenous progenitors/stem cells activation. So by investigating the presence and properties of such cells in mammals especially human, one could possibly harness those cells toward regeneration including neurons. We conducted RNA profiling to compare human vs mouse stem cell niche and lesioned vs non lesioned spinal cord mouse stem cell niche. This niche is particularly interesting as in anamniotes, radial ependymoglia cells located in this region are multipotent and can generate new motoneurons after lesion. And similar, albeit non identical, cells are present in mouse. In mammals, after lesion, these niche cells actively proliferate and migrate to generate mainly astrocytic cells and few oligodendrocytes which participate to the glial scar and regeneration by providing neurotrophic factor such as CNTF, HGF, and IGF-1. This niche contains at least 5 cell types and here a new dorsal cell type expressing Msx1 and Id4 transcription factors was identified. These results indicated that the adult spinal cord niche in mouse and human is a mosaic of cells with different developmental origin and maintaining high levels of neural developmental genes. Glial-neuronal interactions supporting and keeping neurons intact can be influence neurodegenerative diseases. One of these glial cells is the satellite oligodendrocyte or so called perineuronal satellite cells (PNCs). PNCs are tightly associated to the soma of large neurons and widely spread in the grey matter of the CNS both cortex and spinal cord. However the cellular properties and functional roles of these unmyelinating oligodendrocytes are not yet discovered. In this study, nestin-GFP positive cells are associated to neurons immunostained for neuronal nuclear antigen in both cortex and spinal cord. We identified PNCs as CNPase positive cells that are neither oligodendrocyte progenitor cells (PDGFRa) nor myelinating oligodendrocytes (MBP). These data suggest that PNCs might affect neuronal survival as well as the myelination process in demyelinating conditions. Also it could be implicated in neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis due to their interaction with motor neurons
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Greer, Kisha Michelle. "Aberrant hippocampal neurogenesis contributes to learning and memory deficits in a mouse model of repetitive mild traumatic brain injury." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/94329.
Full textAbstract:
Adult hippocampal neurogenesis, or the process of creating new neurons in the dentate gyrus (DG) of the hippocampus, underlies learning and memory capacity. This cognitive ability is essential for humans to operate in their everyday lives, but cognitive disruption can occur in response to traumatic insult such as brain injury. Previous findings in rodent models have characterized the effect of moderate traumatic brain injury (TBI) on neurogenesis and found learning and memory shortfalls correlated with limited neurogenic capacity. While there are no substantial changes after one mild TBI, research has yet to determine if neurogenesis contributes to the worsened cognitive outcomes of repetitive mild TBI. Here, we examined the effect of neurogenesis on cognitive decline following repetitive mild TBI by utilizing AraC to limit the neurogenic capacity of the DG. Utilizing a BrdU fate-labeling strategy, we found a significant increase in the number of immature neurons that correlate learning and memory impairment. These changes were attenuated in AraC-treated animals. We further identified endothelial cell (EC)-specific EphA4 receptor as a key mediator of aberrant neurogenesis. Taken together, we conclude that increased aberrant neurogenesis contributes to learning and memory deficits after repetitive mild TBI.Doctor of Philosophy
In the United States, millions of people experience mild traumatic brain injuries, or concussions, every year. Patients often have a lower ability to learn and recall new information, and those who go on to receive more concussions are at an increased risk of developing long-term memory-associated disorders such as dementia and chronic traumatic encephalopathy. Despite the high number of athletes and military personnel at risk for these disorders, the underlying cause of long-term learning and memory shortfalls associated with multiple concussions remains ill defined. In the brain, the hippocampus play an important role in learning and memory and is one of only two regions in the brain where new neurons are created from neural stem cells through the process of neurogenesis. Our study seeks to address the role of neurogenesis in learning and memory deficits in mice. These findings provide the foundation for future, long-term mechanistic experiments that uncover the aberrant or uncontrolled processes that derail neurogenesis after multiple concussions. In short, we found an increase in the number of newborn immature neurons that we classify as aberrant neurogenesis. Suppressing this process rescued the learning and memory problems in a rodent model of repeated concussion. These findings improve our understanding of the processes that contribute to the pathophysiology of TBI.
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Greer, Kisha. "Aberrant hippocampal neurogenesis contributes to learning and memory deficits in a mouse model of repetitive mild traumatic brain injury." Diss., Virginia Tech, 2019. http://hdl.handle.net/10919/94329.
Full textAbstract:
Adult hippocampal neurogenesis, or the process of creating new neurons in the dentate gyrus (DG) of the hippocampus, underlies learning and memory capacity. This cognitive ability is essential for humans to operate in their everyday lives, but cognitive disruption can occur in response to traumatic insult such as brain injury. Previous findings in rodent models have characterized the effect of moderate traumatic brain injury (TBI) on neurogenesis and found learning and memory shortfalls correlated with limited neurogenic capacity. While there are no substantial changes after one mild TBI, research has yet to determine if neurogenesis contributes to the worsened cognitive outcomes of repetitive mild TBI. Here, we examined the effect of neurogenesis on cognitive decline following repetitive mild TBI by utilizing AraC to limit the neurogenic capacity of the DG. Utilizing a BrdU fate-labeling strategy, we found a significant increase in the number of immature neurons that correlate learning and memory impairment. These changes were attenuated in AraC-treated animals. We further identified endothelial cell (EC)-specific EphA4 receptor as a key mediator of aberrant neurogenesis. Taken together, we conclude that increased aberrant neurogenesis contributes to learning and memory deficits after repetitive mild TBI.Doctor of Philosophy
In the United States, millions of people experience mild traumatic brain injuries, or concussions, every year. Patients often have a lower ability to learn and recall new information, and those who go on to receive more concussions are at an increased risk of developing long-term memory-associated disorders such as dementia and chronic traumatic encephalopathy. Despite the high number of athletes and military personnel at risk for these disorders, the underlying cause of long-term learning and memory shortfalls associated with multiple concussions remains ill defined. In the brain, the hippocampus play an important role in learning and memory and is one of only two regions in the brain where new neurons are created from neural stem cells through the process of neurogenesis. Our study seeks to address the role of neurogenesis in learning and memory deficits in mice. These findings provide the foundation for future, long-term mechanistic experiments that uncover the aberrant or uncontrolled processes that derail neurogenesis after multiple concussions. In short, we found an increase in the number of newborn immature neurons that we classify as aberrant neurogenesis. Suppressing this process rescued the learning and memory problems in a rodent model of repeated concussion. These findings improve our understanding of the processes that contribute to the pathophysiology of TBI.
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Webber, Daniel. "Therapeutic potential of transplanted neural progenitor cells following injury to the central nervous system." Thesis, King's College London (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439085.
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Forbes, Lindsey. "Using human iPSC-derived neural progenitor cells to increase integrin expression in the CNS." Thesis, University of St Andrews, 2018. http://hdl.handle.net/10023/16567.
Full textAbstract:
Repair of the adult mammalian spinal cord is prohibited by several extrinsic and intrinsic factors. As the CNS matures, growth-promoting proteins such as integrins are developmentally downregulated resulting in a reduced capacity for axonal outgrowth. Integrins are heterodimeric receptors involved in cell-cell and cell-matrix interactions. Specifically, within mature corticospinal tract (CST) axons, integrins are not transported into the axonal compartment. One integrin heterodimer, α9β1, is of particular interest for its ability to promote neurite outgrowth when bound to a component of the injury-induced milieu, tenascin-C. This project aimed to increase integrin expression within the CNS using induced pluripotent stem cell-derived human neural progenitor cells (iPSC-hNPCs). Using immunocytochemistry and western blotting, endogenous integrin expression within iPSC-hNPCs was determined. In addition, overexpression of α9 integrin was achieved using transfection and lentiviral transduction. The capacity of wild type (WT) and α9-hNPCs to extend neurites on tenascin-C was assessed using neurite outgrowth assays. Results revealed increasing α9 integrin expression in hNPCs significantly promoted neurite outgrowth when cultured on tenascin-C. Interestingly, increasing the concentration of human tenascin-C, resulted in increasingly longer neurites from WT hNPCs suggesting hNPCs could actively upregulate integrin expression. Subsequently, WT and α9-hNPCs were transplanted into layer V of the neonatal rat sensorimotor cortex, which projects to the CST. WT and α9-hNPCs survived up to 8 weeks post-transplantation and produced projections along white matter tracts, including areas of the CST. Additionally, hNPCs retained α9-eYFP protein expression in vivo over time and was localised within axonal projections. These results highlight the capabilities of iPSC-hNPCs to promote integrin expression within the rodent CNS presenting one potential avenue to target neuronal replacement following spinal injury. Future research should focus on assessing the regenerative capacity of WT and α9-hNPCs within an injury model concentrating on the ability of these cells to adapt within an injured environment.
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Milosevic, Javorina, Sigrid C. Schwarz, Vera Ogunlade, Anne K. Meyer, Alexander Storch, and Johannes Schwarz. "Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-184308.
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Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs) and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.
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Li, Hang. "Neural Stem/Progenitor Cell 3-D Differentiation for Repair of Central Nervous System Injuries." University of Akron / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=akron1428248647.
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Milosevic, Javorina, Sigrid C. Schwarz, Vera Ogunlade, Anne K. Meyer, Alexander Storch, and Johannes Schwarz. "Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation." Biomed Central, 2009. https://tud.qucosa.de/id/qucosa%3A28998.
Full textAbstract:
Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs) and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.
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Carter, Calvin Stanley. "Characterizing the role of primary cilia in neural progenitor cell development and neonatal hydrocephalus." Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/4587.
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Neonatal hydrocephalus is a common neurological disorder leading to expansion of the cerebral ventricles. This disease is associated with significant morbidity and mortality and is often fatal if left untreated. Hydrocephalus was first described over 2500 years ago by Hippocrates, the father of medicine, and remains poorly understood today. Current therapies still rely on invasive procedures developed over 60 years ago that are associated with high failure and complication rates. Thus, the identification of molecular mechanisms and the development of non-invasive medical treatments for neonatal hydrocephalus are high priorities for the medical and scientific communities. The prevailing doctrine in the field is that hydrocephalus is strictly a "plumbing problem" caused by impaired cerebrospinal fluid (CSF) flow. Recently, animal models with impaired cilia have provided insight into the mechanisms involved in communicating (non-obstructive) hydrocephalus. However, as a result of a poor understanding of hydrocephalus, no animal studies to date have identified an effective non-invasive treatment.
The goal of this thesis project is to investigate the molecular mechanisms underlying this disease and to identify a non-invasive, highly effective treatment strategy.
In Chapter 2, we utilize a novel animal model with idiopathic hydrocephalus, mimicking the human ciliopathy Bardet-Biedl Syndrome (BBS), to examine the role of cilia in hydrocephalus. We find that these mice develop communicating hydrocephalus prior to the development of ependymal "motile" cilia, suggesting that this phenotype develops as a result of dysfunctional "primary" cilia. Primary cilia are non-motile and play a role in cellular signaling. These results challenge the current dogma that dysfunctional motile cilia underlies neonatal hydrocephalus and implicate a novel role for primary cilia and cellular signaling in this disease.
Chapter 3 focuses on identifying the link between primary cilia and neonatal hydrocephalus. In this chapter, we report that disrupting the molecular machinery within primary cilia leads to faulty PDGFRα signaling and the loss of a particular class of neural progenitor cells called oligodendrocyte precursor cells (OPCs). We find that the loss of OPCs leads to neonatal hydrocephalus. Importantly, we identify the molecular mechanism underlying both the loss of OPCs and the pathogenesis of neonatal hydrocephalus.
Chapter 4 explores the therapeutic potential of targeting the defective cellular signaling pathways to treat neonatal hydrocephalus. By targeting the faulty signaling, we restore normal development of oligodendrocyte precursor cells, and curtail the development of hydrocephalus. This work challenges the predominant view of hydrocephalus being strictly a "plumbing problem" treatable solely by surgical diversion of CSF. Here, we propose that hydrocephalus is a neurodevelopmental disorder that can be ameliorated by non-invasive means. Importantly, we introduce novel molecular targets and a non-invasive treatment strategy for this devastating disorder. To our knowledge, we are the first to successfully treat neonatal hydrocephalus in any model organism by targeting neural progenitor cells.