Дисертації: "Induced-neural stem cells"

1

Vicario, Nunzio. "Directly induced Neural Stem Cells transplantation and prospects for stem cell-based therapy." Doctoral thesis, Università di Catania, 2017. http://hdl.handle.net/10761/4088.

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Despite the remarkable beneficial effects of disease-modifying agents in relapsing-remitting multiple sclerosis (MS) patients, progressive forms of (P)MS still lack effective treatments. This stark contrast is partially dependent on the difficulties researchers have found in tackling the complex pathophysiology of this phase of disease, in which chronic inflammation within the central nervous system (CNS) is coupled by ongoing neurodegeneration and demyelination. Cell transplantation is among the most promising therapeutic approaches in regenerative medicine, combining tissue trophic and immunomodulatory effects of the graft with its intrinsic potential for cellreplacement. These are all attributes that can be harnessed to treated patients with PMS. As such, within this thesis, I have focused my attention on investigating how cellular therapies could be used to (i) prevent neuronal damage, (ii) modulate the chronic activation of the immune system and (iii) replace the damaged myelin in PMS. Olfactory Ensheathing Cells (OECs) are a special population of glial cells known to exert neuroprotective mechanisms and capable of promoting neuroprotection. Using in vitro models of neuron-like cells, I have demonstrated that OECs exert their neuroprotective effect by reducing Cx43-mediated cell-to-cell and cell-toextracellular environment communications. Despite this important finding, the immunomodulatory and remyelinating potential of OECs is still limited. As such, I decided to study a complementary stem cell approach that conjugates these attributes with ease in clinical applicability. Induced Neural Stem Cells (iNSCs) are a source of autologous, stably expandable, tissue specific and easily accessible stem cells, which have the potential to differentiate into the three main neural lineages. Mouse iNSCs were characterized in vitro and in vivo and their immunomodulatory potential was initially studied. This work uncovered a novel mechanism that underpins the potential of iNSCs to interact with the chronic CNS compartmentalised activation of the innate immune system. Specifically, I found that iNSCs are able to sense extracellular metabolites, which accumulate in the chronically inflamed CNS, and to ameliorate neuroinflammation via succinate-SUCNR1-dependend mechanisms. To characterize the potential for tissue replacement and remyelination of such a promising cell line, I have also analysed how iNSCs grafts differentiate in an experimental model of focal demyelination. I found that iNSCs are able to integrate and differentiate into remyelinating oligodendrocytes (OLs) in chronic demyelinated CNS. These data suggest that iNSCs are indeed an effective source of stem cell transplantation, being able to modulate inflammation and to effectively replace lost tissue in mouse models of PMS. Altogether the evidences gathered in this thesis are important new steps in the field of cell transplantation, which will be pivotal in the march forward for future clinical applications in chronic demyelinating CNS disorders.

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2

Yoshimatsu, Masayoshi. "In vivo regeneration of rat laryngeal cartilage with mesenchymal stem cells derived from human induced pluripotent stem cells via neural crest cells." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265189.

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京都大学
新制・課程博士
博士(医学)
甲第23417号
医博第4762号
新制||医||1052(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授松田秀一特定拠点, 教授妻木範行, 教授安達泰治
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM

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3

Cullen, Daniel Kacy. "Traumatically-induced degeneration and reactive astrogliosis in three-dimensional neural co-cultures." Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-11282005-210117/.

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Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2006.
Robert McKeon, Committee Member ; Robert Lee, Committee Member ; Robert Guldberg, Committee Member ; Ravi Bellamkonda, Committee Member ; Michelle LaPlaca, Committee Chair. Vita.

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4

McLaughlin, Heather Ward. "Modeling sporadic Alzheimer's disease using induced pluripotent stem cells." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13094355.

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Despite being the leading cause of neurodegeneration and dementia in the aging brain, the cause of Alzheimer's disease (AD) remains unknown in most patients. The terminal pathological hallmarks of abnormal protein aggregation and neuronal cell death are well-known from the post-mortem brain tissue of Alzheimer's disease patients, but research into the earliest stages of disease development is hindered by limited model systems. In this thesis, an in vitro human neuronal system was derived from induced pluripotent stem (iPS) cell lines reprogrammed from dermal fibroblasts of AD patients and age-matched controls. This allows us to investigate the cellular mechanisms of AD neurodegeneration in the human neurons of sporadic AD (SAD) patients, whose development of the disease cannot be explained by our current understanding of AD. We show that neural progenitors and neurons derived from SAD patients show an unexpected expression profile of enhanced neuronal gene expression resulting in premature differentiation in the SAD neuronal cells. This difference is accompanied by the decreased binding of the repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) transcriptional inhibitor of neuronal differentiation in the SAD neuronal cells. The SAD neuronal cells also have increased production of \(amyloid-\beta\) and higher levels of tau protein, the main components of the plaques and tangles in the AD brain.

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5

Ma, Shuang. "Preoptic Regulatory Factor 2 Inhibits Proliferation and Enhances Drug Induced Apoptosis in Neural Stem Cells." View abstract, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3353557.

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6

Alyamani, Najiah. "Molecular-genetics studies of organophosphate induced neurodegeneration in differentiating mammalian cell lines and neural progenitor stem cells." Thesis, Nottingham Trent University, 2018. http://irep.ntu.ac.uk/id/eprint/35003/.

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Organophosphorus (OP) pesticides are widely used despite evidence they cause neurotoxicity after exposure. The primary target for OPs is acetylcholinesterase, but there is evidence they can inhibit other cellular proteins including cytoskeletal and axon growth associated proteins, which are implicated in nervous system development. Furthermore, little is known about the ability of OPs to cause genotoxicity. The objectives of this study were to evaluate the effects of selected OPs on neurite outgrowth, expression of cytoskeletal proteins and associated gene expression levels, and to investigate histone deacetylation (HDAC) activity in three types of differentiating cell models. The initial findings indicated that cell viability was unaffected by exposure to 1, 3 and 10 µM CPF, CPO and PSP in N2a and C6 cells. A high content assay was sensitive enough to rapidly detect and quantify morphological changes, including inhibition of neurite number and length. Western blot and ELISA analysis in N2a and C6 cells revealed reduced levels of the selected cytoskeletal and associated regulatory proteins (MAP-2, Tau, βIII-tubulin, GAP43, NFH and GFAP) following the treatment with at least one concentration of CPF, CPO and PSP, which could be linked to the inhibition of neurite outgrowth. Using quantitative RT-PCR analysis on the total RNA of the genes MAP-2, TUBB3, MAPT, NEFH, GAP-43, and GFAP showed a good correlation between the altered protein expression and regulation of gene levels for most markers, which suggests these OPs can cause genotoxic effects. Increased levels of HDAC activity were observed for all OPs in rodent cell lines, suggesting that epigenetic effects may be at least partly involved in some gene expression changes. RT-PCR analysis of TUBB3, NEFH, and GFAP was also carried out in ReNcell CX cells, a co-culture of neuronal and glial cells, and showed down-regulation of gene levels for at least one concentration of all the OPs, as well as increasing the level of HDAC activity in a similar pattern to the results for N2a and C6 cells. Taken together, the data in this thesis suggest a novel action of OPs altering HDAC activity, which can be correlated to some of the observed changes in gene and protein levels of selected cytoskeletal and associated regulatory proteins that can be linked to the observed disruption of neurite outgrowth and neural development. Further work is needed to identify other molecular targets invoved in these phenomena, particularly when there is no correlation with HDAC activity changes.

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7

Joshi, Ramila Joshi. "Micro-engineering of embryonic stem cells niche to regulate neural cell differentiation." University of Akron / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=akron1544029342969082.

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8

Kandasamy, Majury [Verfasser], Andreas [Gutachter] Faissner, and Beate [Gutachter] Brand-Saberi. "Investigations on the generation of neural stem cells derived from human induced pluripotent stem cells / Majury Kandasamy ; Gutachter: Andreas Faissner, Beate Brand-Saberi." Bochum : Ruhr-Universität Bochum, 2017. http://d-nb.info/113135463X/34.

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9

Marzec-Schmidt, Katarzyna. "Deep convolutional neural networks accurately predict the differentiation status of human induced pluripotent stem cells." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-19420.

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Rapid progress of AI technology in the life science area is observed in recent years. Convolutionalneural network (CNN) models were successfully applied for the localization and classification of cellson microscopic images. Induced pluripotent stem cells are one of the most important innovations inbiomedical research and are widely used, e.g. in regenerative medicine, drug screening, and diseasemodeling. However, assessment of cell cultures’ quality requires trained personnel, is timeconsumingand hence expensive. Fluorescence microscope images of human induced pluripotentstem‐hepatocytes (hiPS‐HEPs) derived from three human induced pluripotent stem cell (hiPSC) lineswere taken daily from day 1 until day 22 of differentiation. The cells from day 1 to 14 were classifiedas ´Early differentiation´, and above day 16 as ´Late differentiation´. In this study, it wasdemonstrated that a CNN‐based model can be trained with simple fluorescence microscope imagesof human induced pluripotent stem‐hepatocytes, and then used to predict with high accuracy(96.4%) the differentiation stage of an independent new set of images.

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10

Cullen, Daniel Kacy. "Traumatically-Induced Degeneration and Reactive Astrogliosis in 3-D Neural Co-Cultures: Factors Influencing Neural Stem Cell Survival and Integration." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/7584.

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Traumatic brain injury (TBI) results from a physical insult to the head and often results in temporary or permanent brain dysfunction. However, the cellular pathology remains poorly understood and there are currently no clinically effective treatments. The overall goal of this work was to develop and characterize a novel three-dimensional (3-D) in vitro paradigm of neural trauma integrating a robust 3-D neural co-culture system and a well-defined biomechanical input representative of clinical TBI. Specifically, a novel 3-D neuronal-astrocytic co-culture system was characterized, establishing parameters resulting in the growth and vitality of mature 3-D networks, potentially providing enhanced physiological relevance and providing an experimental platform for the mechanistic study of neurobiological phenomena. Furthermore, an electromechanical device was developed that is capable of subjecting 3-D cell-containing matrices to a defined mechanical insult, with a predicted strain manifestation at the cellular level. Following independent development and validation, these novel 3-D neural cell and mechanical trauma paradigms were used in combination to develop a mechanically-induced model of neural degeneration and reactive astrogliosis. This in vitro surrogate model of neural degeneration and reactive astrogliosis was then exploited to assess factors influencing neural stem cell (NSC) survival and integration upon delivery to this environment, revealing that specific factors in an injured environment were detrimental to NSC survival. This work has developed enabling technologies for the in vitro study of neurobiological phenomena and responses to injury, and may aid in elucidating the complex biochemical cascades that occur after a traumatic insult. Furthermore, the novel paradigm developed here may provide a powerful experimental framework for improving treatment strategies following neural trauma, and therefore serve as a valid pre-animal test-bed.

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11

Yoshikawa(Ogura), Aya. "γ-Secretase Inhibitors Prevent Overgrowth of Transplanted Neural Progenitors Derived from Human-Induced Pluripotent Stem Cells". Kyoto University, 2013. http://hdl.handle.net/2433/174829.

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12

Glover, Hannah Jacquilyn. "L-proline-induced transition of mouse ES cells to a spatially distinct primitive ectoderm-like cell population primed for neural differentiation." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20576.

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Naïve mouse embryonic stem cells (mESCs) derived from the preimplantation mouse blastocyst self-renew in the presence of LIF and BMP4. These cells are pluripotent, meaning they have the ability to differentiate into the ~200 cell types of the developing embryo and adult. Naïve mESCs are one discrete state along a pluripotency continuum – delimited by ground-state mESCs as the earliest cell population, followed by naïve mESCs, and with EpiSCs as the most ‘primed’ population. The amino acid L-proline has novel growth factor-like properties during development - from improving blastocyst development to driving neurogenesis. Addition of 400 μM L-proline to naïve mESCs produces a pluripotent cell population between naïve mESCs and EpiSCs. These cells, named early primitive ectoderm-like (EPL) cells, recapitulate in vivo development of the pre-implantation inner cell mass to the postimplantation primitive ectoderm. EPL cells maintain expression of the naïve marker Rex1 and upregulate expression of the primitive ectoderm genes Dnmt3b and Fgf5. This thesis identifies mechanisms underpinning L-proline-mediated differentiation to EPL cells, including a complex self-regulating signalling network involving the MAPK, Fgfr, PI3K and mTOR pathways. Statistical models were used to understand the contributions of individual signalling pathways to changes in colony morphology, cell number, gene expression, proliferation and apoptosis. Other mechanisms underpinning the naïve mESCs-to-EPL cell transition were explored, including DNA methylation, histone acetylation, proline synthesis and metabolism. In addition to expressing primed pluripotency genes, EPL cells upregulate genes associated with neurogenesis, whereas EpiSCs express genes associated with cardiovascular development. When mapped to the 7.0 dpc embryo, EPL cells and EpiSCs represent spatially distinct cell populations. This suggests that after cells transition from naïve mESCs, they diverge and are fated to become either ectoderm (from EPL cells), or mesendoderm (from EpiSCs). This thesis also explored whether L-proline plays an underappreciated role in existing neural differentiation protocols. mESCs cultured in custom N2B27 medium without L-proline had reduced selective cell death resulting in a larger yield of Sox1+ neurectoderm.

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13

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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14

Ngamjariyawat, Anongnad, Kyril Turpaev, Svitlana Vasylovska, Elena N. Kozlova, and Nils Welsh. "Co-Culture of Neural Crest Stem Cells (NCSC) and Insulin Producing Beta-TC6 Cells Results in Cadherin Junctions and Protection against Cytokine-Induced Beta-Cell Death." Uppsala universitet, Neuroanatomi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-198839.

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PURPOSE: Transplantation of pancreatic islets to Type 1 diabetes patients is hampered by inflammatory reactions at the transplantation site leading to dysfunction and death of insulin producing beta-cells. Recently we have shown that co-transplantation of neural crest stem cells (NCSCs) together with the islet cells improves transplantation outcome. The aim of the present investigation was to describe in vitro interactions between NCSCs and insulin producing beta-TC6 cells that may mediate protection against cytokine-induced beta-cell death. PROCEDURES: Beta-TC6 and NCSC cells were cultured either alone or together, and either with or without cell culture inserts. The cultures were then exposed to the pro-inflammatory cytokines IL-1β and IFN-γ for 48 hours followed by analysis of cell death rates (flow cytometry), nitrite production (Griess reagent), protein localization (immunofluorescence) and protein phosphorylation (flow cytometry). RESULTS: We observed that beta-TC6 cells co-cultured with NCSCs were protected against cytokine-induced cell death, but not when separated by cell culture inserts. This occurred in parallel with (i) augmented production of nitrite from beta-TC6 cells, indicating that increased cell survival allows a sustained production of nitric oxide; (ii) NCSC-derived laminin production; (iii) decreased phospho-FAK staining in beta-TC6 cell focal adhesions, and (iv) decreased beta-TC6 cell phosphorylation of ERK(T202/Y204), FAK(Y397) and FAK(Y576). Furthermore, co-culture also resulted in cadherin and beta-catenin accumulations at the NCSC/beta-TC6 cell junctions. Finally, the gap junction inhibitor carbenoxolone did not affect cytokine-induced beta-cell death during co-culture with NCSCs. CONCLUSION: In summary, direct contacts, but not soluble factors, promote improved beta-TC6 viability when co-cultured with NCSCs. We hypothesize that cadherin junctions between NCSC and beta-TC6 cells promote powerful signals that maintain beta-cell survival even though ERK and FAK signaling are suppressed. It may be that future strategies to improve islet transplantation outcome may benefit from attempts to increase beta-cell cadherin junctions to neighboring cells.

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Makedonopoulou, Paraskevi. "Studying the molecular consequences of the t(1;11) balanced translocation using iPSCs derived from carriers and within family controls." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25871.

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Schizophrenia is a major psychiatric disorder that affects 1% of the world population and is among the 10 leading worldwide causes of disability. Disrupted-In- Schizophrenia (DISC1) is one of the most studied risk genes for mental illness and is disrupted by a balanced translocation between chromosomes 1 and 11 that co-segregates with major mental illness in a single large Scottish family. DISC1 is a scaffold protein with numerous interactors and has been shown to hold key roles in neuronal progenitor proliferation, migration, cells signalling and synapse formation and maintenance. The studies herein provide the platform in order to investigate the molecular and cellular consequences of the t(1;11) translocation using induced pluripotent stem cells (iPSCs)-derived neural precursor cells and neurons from within-family carriers and controls. Towards this end, several iPSC lines have been converted into neural progenitor cells (NPCs) and differentiated into physiologically active forebrain neurons following well-characterised protocols. These cells were characterised in terms of basic marker expression at each developmental stage. Inter-line variation was observed in all subsequent experiments but overall t(1;11) lines did not generate less neuronal or less proliferating cells compared to control lines. Furthermore, the expression pattern of genes disrupted by the t(1;11) translocation was investigated by RT-qPCR. DISC1 was reduced by ~50% in the translocation lines, both neural precursors and neurons. This observation corresponds to previous findings in lymphoblastoid cell lines (LBCs) derived from members of the same family. Moreover, DISC1 expression was found to increase as neural precursors differentiation to neurons. Two other genes are disrupted by the t(1;11) translocation;DISC2 and DISC1FP1. Their expression was detectable, but below the threshold of quantification. Similarly, DISC1/DISC1FP1 chimeric transcripts corresponding to such transcripts previously identifies in LBCs from the family were detectable, but not quantifiable. A fourth gene, TSNAX, was also investigated because it is located in close proximity to, and undergoes intergenic splicing with, DISC1. Interestingly, TSNAX was found to be altered in some but not all time points studied, in the translocation carriers compared to control lines. In addition to breakpoint gene expression profiling, iPSC-derived material was used to investigate neuronal differentiation. There seemed to be attenuation in BIII-TUBULIN expression at two weeks post-differentiation, while NESTIN, MAP2 and GFAP expression was similar between translocation carrier and control lines at all time points studied. I also had access to targeted mice designed to mimic the derived chromosome 1 of the t(1;11) balanced translocation. Using RT-qPCR Disc1 expression was found to be 50% lower in heterozygous mice compared to wild types, and I detected a similar profile of chimeric transcript expression as detected in translocation carrier-derived LBCs. These observations support my gene expression studies of the human cells and indicate that the iPSC-derived neural precursors and neurons can be studied in parallel with the genome edited mice to obtain meaningful insights into the mechanism by which the t(1;11) translocation confers substantially elevated risk of major mental illness. In conclusion, the studies described in this thesis provide an experimental platform for investigation of the effects of the t(1;11) translocation upon function and gene and protein expression in material derived from translocation carriers and in brain tissue from a corresponding mouse model.

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16

Cheng, Tianci [Verfasser], and Matthias [Akademischer Betreuer] Morgalla. "GABAergic neural stem cells transplantation after spinal cord injury induced chronic neuropathic pain in a rat model / Tianci Cheng ; Betreuer: Matthias Morgalla." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1182985920/34.

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17

Camnasio, S. "IL RUOLO DELL¿HUNTINGTINA NELLA FISIOLOGIA DEL DIFFERENZIAMENTO NEURONALE E NELLA PATOLOGIA." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229428.

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Huntingtin (htt) is the 3,144 amino acid protein whose mutation causes Huntington’s disease (HD). Mutant htt is toxic for brain neurons, but the mechanism leading to pathology is still far from being understood. Moreover, since loss of wild type (WT) htt contributes to pathogenesis, the study of htt’s role and the effect of its depletion, in the central nervous system becomes important. In this Thesis we analyse complementarily the role of WT and mutant htt in physiological and pathological conditions. In the first part, it is described a novel role of WT htt during neural development. This field is still quite unexplored, and, even if the function of protein has been largely described during post-natal life (when HD onset occurs), there are recent evidences that also normal development could be altered in htt depletion condition. Specifically it has been investigated the role of htt in establishment and maintenance of neuroepithelial apico-basal polarity and, as a result, in the regulation of neural progenitors cell fate decision. We demonstrate that htt, through cooperation with polarity protein aPKC, contributes to regulation of polarity mechanism during early neurogenesis. In the second part of the Thesis it is described the establishment of a human in vitro model of HD, thanks to somatic cell reprogramming technology. We report the generation of a series of induced pluripotent stem (iPS) cells derived from several patients. HD-iPS cells have the potential to be differentiated to the neuronal population that degenerate during disease progression, holding the identical genetic information of the donor. Starting also from rare homozygous patient, and demonstrating mutation related enhanced lysosomal activity, our work is the first that describes a cohort of HD-iPS cells and their phenotypical characterization.

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18

Cho, Taesup. "Neural stem cell transplantation : neuroprotection and LTP-induced facilitation of neurogenesis." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36960.

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Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in the Alzheimer’s disease (AD) brain are largely unknown and a primary objective of this work is to demonstrate possible efficacy of NPC administration in an AD animal model. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons, conferring neuroprotection with enhancement of neurotrophic factors, and diminishing levels of neurotoxic agents. Additionally, since chronic inflammation is a characteristic property of the AD brain, I considered NPC transplantation could have a particular utility in inhibiting ongoing inflammatory reactivity. Accordingly, intra-hippocampal transplantation of NPC has been examined for efficacy in attenuating inflammatory responses and conferring neuroprotection in the hippocampus. These findings indicate efficacy for NPC transplantation with effects consistent with cellular actions to attenuate inflammatory reactivity. Synaptic plasticity, such as long-term potentiation (LTP), is thought to play a critical role in modification of neuronal circuitry in learning and memory, but the role in neurogenesis is not well known. A critical aspect of my study was to examine potential roles of N-methyl-D-aspartate receptor (NMDAR)-dependent LTP in promoting neurogenesis by facilitating proliferation/survival and neuronal differentiation of endogenous NPCs in the dentate gyrus (DG) and exogenously transplanted neural stem cells (NSCs) in the CA1. I found that LTP induction significantly facilitates proliferation/survival and neuronal differentiation of endogenous NPCs and exogenously transplanted NSCs in the hippocampus. These effects were eliminated by a NMDAR competitive antagonist, CPP. Accordingly, chemical LTP stimulation reproduced enhanced proliferation/survival and neuronal differentiation of NSCs when co-cultured with hippocampal neurons. These effects were eliminated by a NMDAR competitive antagonist, D-APV and inhibited by the tyrosine kinase inhibitor, K252a. ELISA and biotinylation results revealed that NMDAR-mediated LTP facilitates the release of a neurotrophic factor, BDNF. The conditioned media from cLTP-induced hippocampal neurons were sufficient to activate the BDNF receptor, TrkB. Overall, my results suggest that NMDAR-dependent LTP plays a critical role in neurogenesis and may contribute to the utility of NSC transplantation as an effective cell therapy for a variety of neurodegenerative diseases.

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19

Yulius, Hermanto. "Transplantation of feeder-free human induced pluripotent stem cell-derived cortical neuron progenitors in adult male Wistar rats with focal brain ischemia." Kyoto University, 2019. http://hdl.handle.net/2433/242389.

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20

Nishimura, Koji. "Transplantation of murine induced pluripotent stem cell-derived neural progenitors into the cochlea." Kyoto University, 2012. http://hdl.handle.net/2433/157416.

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21

Hadoux, Julien. "Modélisation des néoplasies endocriniennes multiples de type II par les cellules souches pluripotentes induites porteuses de mutations germinales du gène RET." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS389/document.

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Les cellules souches pluripotentes induites (CSPi) permettent la modélisation de processus avec, en oncologie, un intérêt potentiel pour la modélisation de syndromes de prédisposition au cancer liés à des mutations germinales d’oncogènes. Nous avons généré des lignées de CSPi à partir de patients atteints de néoplasies endocriniennes multiples de type 2 (NEM2), porteurs de mutations germinales du gène RET : RETC620R, RETC634Y et RETM918T. Nous avons généré une CSPi RETY634C, contrôle isogénique, par correction de la mutation RETC634Y via CRSPR/Cas9. Ces CSPi présentent tous les critères de pluripotence avec un caryotype normal et expriment Ret. L’étude histologique approfondie des tératomes a mis en évidence le développement de cellules C en leur sein et également de cellules neuroendocrines exprimant la Chromogranine A mais sans aspect d’hyperplasie des cellules C ou de carcinome médullaire de la thyroïde ni de tumeur neuroendocrine réminiscente du phénotype des NEM2. L’analyse comparative de l’expression des gènes de ces CSPi a mis en évidence, dès le stade de pluripotence, une activation du réseau transcriptionnel du gène EGR1 qui pourrait constituer un des mécanismes moléculaires responsables de la mise en place du phénotype des NEM2. La différenciation en cellules souches de la crête neurale (CSCN), cellules d’origine cibles des tumeurs développées dans le cadre des NEM2, en particulier le phéochromocytome, était efficace et reproductible pour toutes nos lignées. Nous avons mis en évidence l’activation d’un programme commun invasif au niveau des CSCN avec mutation RETC634Y et RETM918T ainsi qu’une forte dérégulation du réseau des intégrines entraînant une forte dérégulation de l’adhésion cellulaire. Ceci était confirmé par une augmentation des capacités de migration CSCN avec mutation de RET par rapport aux CSCN témoins. Ainsi, la génération de CSPi avec mutation de RET a permis d’identifier des voies de signalisation potentiellement impliquées dans la physiopathologie des NEM2 et constitue une première étape vers la modélisation des NEM2 in vitro
Induced pluripotent stem cell (iPSC) offer major perspectives in disease modelling and, in the oncology field, can be used for modelling cancer predisposition syndromes. We generated IPSC lines from somatic cells of patients with multiple endocrine neoplasia type 2 (MEN2) who harboured germline mutations in the RET gene: RETC620R, RETC634Y et RETM918T. We have also generated an isogenic RETY634C iPSC control line by genome engineering using CRSPR/Cas9-mediated method to "correct” C634Y mutation. All iPSC lines exhibited all markers of pluripotency with a normal karyotype and expressed Ret. A thorough histological study of teratomas from these iPSC highlighted the development of C cells and Chromogranin A-expressing neuroendocrine cells within them but without C-cell hyperplasia, medullary thyroid carcinoma or neuroendocrine tumours reminiscent of MEN2 phenotype. Comparative gene expression analysis revealed an activation of the EGR1 transcriptional network, at the pluripotent stem cell stage which could be one of the molecular effector of the phenotype. Neural crest stem cell (NCSC), the cell of origin of some of the tumoral features of MEN2, could be differentiated in vitro from all our RET-mutated iPSC lines effectively. Gene expression analysis revealed an activation of cell invasion program in RETC634Y and RETM918T–mutated NCSC and a deregulation of integrin network causing a strong deregulation of cell adhesion which was confirmed with increased migration capabilities in vitro. Thus, the generation of the first RET-mutated iPSCs allowed the identification of signalling pathways potentially implicated in the pathophysiology of MEN2 and constitute a first step in modelling these tumours in vitro

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22

Zhang, Qi [Verfasser]. "Immunohistochemical Study of Spinal Cord Injury Induced Neuropathic Pain with GABAergic Neural Stem Cell Transplantation Treatment / Qi Zhang." Tübingen : Universitätsbibliothek Tübingen, 2021. http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1190103.

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23

Mokrani, Sofiane. "Maintenance de la stabilité chromosomique des cellules souches neurales murines au cours du développement et après un stress génotoxique aiguë ou chronique Impaired brain development and behavior of Xlf null mice linked to chromosome instability-induced premature neurogenesis Higher Chromosome Stability in Mouse Embryonic Neural Stem and Progenitor Cells than in Fibroblasts in Response to Acute or Chronic Genotoxic Stress." Thesis, Institut polytechnique de Paris, 2019. http://www.theses.fr/2019IPPAX010.

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Une exposition prénatale aux radiations ionisantes est associée au développement de pathologies neurodéveloppementales liées à l’induction de dommages à l’ADN dans les cellules souches et progéniteurs neuraux (CSPN). Ainsi, la stabilité génétique des CSPN est cruciale pour le développement et l’homéostasie du cerveau. Cependant, des altérations génomiques au niveau des CSPN au cours du développement pourraient promouvoir la diversité neuronale. XLF est un composant de la voie de réparation d’ADN par NHEJ (pour Non-Homologous End-Joining). Nous avons montré une augmentation de l’instabilité des CSPN dans le cerveau embryonnaire des souris Xlf-/- qui pourrait perturber la neurogenèse au cours du développement, et ainsi être responsable d’altérations comportementales identifiées chez ces souris à l’âge adulte. A l’aide d’approches cytogénétiques, nous avons comparés la stabilité chromosomique des CSPN et des fibroblastes embryonnaires murins (MEF) exposés à un stress génotoxique aigue (irradiation γ) ou chronique (incorporation de thymidine tritiée dans l’ADN). Nos résultats démontrent que les CSPN maintiennent leur intégrité génétique de façon plus efficace que les MEF. En effet, les CSPN semblent avoir de meilleures capacités de réparation des dommages à l’ADN que les MEF, ce qui leur permet de développer une réponse adaptative à un stress génotoxique chronique. Cette réponse adaptative implique XLF et agit conjointement avec les points de contrôle du cycle cellulaire et l'apoptose pour préserver la stabilité du génome et éliminer les cellules endommagées. L’ensemble de nos résultats apporte la démonstration d’une réponse robuste aux dommages de l'ADN dans les CSPN et souligne l'importance de XLF lors du développement du cerveau
Prenatal exposure to ionizing radiation has been associated with many neurodevelopmental disorders due to the DNA damage induced in neural stem and progenitors cells (NSPC). Thus, genetic stability of NSPC is crucial for brain development and homeostasis. Nevertheless, genomic alterations occurring during development in NSPC may have a potential impact on the physiological neuronal diversity. XLF is a component of the NHEJ (Non-Homologous End-Joining) repair pathway. Here, we show that NSPC from Xlf-/- embryos exhibit increased chromosome instability, leading to premature neurogenesis and consequently neurobehavioral disorders. Using cytogenetic approaches, we compared the chromosome stability of mouse embryonic NSPC and fibroblasts (MEF) exposed to acute (γ-irradiation) or chronic (incorporation of tritiated thymidine into DNA) genotoxic stress. Our results demonstrate the higher capacity of NSPC as compared to MEF to maintain their genomic integrity. We evidenced that NSPC have more efficient DNA repair activity than MEF, allowing them to develop an adaptive response to chronic genotoxic stress. This adaptive response involves XLF and acts together with apoptosis and cell cycle checkpoints to preserve the stability of the genome and to eliminate damaged cells. Altogether, our results provide new insights into the robust DNA damage response in NSPC and highlight the importance of Xlf during brain development

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24

Sun, Jianan. "Protective Effects of Human iPS-Derived Retinal Pigmented Epithelial Cells in Comparison with Human Mesenchymal Stromal Cells and Human Neural Stem Cells on the Degenerating Retina in rd1 Mice." Kyoto University, 2016. http://hdl.handle.net/2433/215387.

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25

Mozafari, Sabah. "Characterization of neural precursors derived from iPSCs in vitro and in vivo after transplantation into the demyelinated central nervous system." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066091/document.

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Les précurseurs neuraux dérivés de cellules souches pluripotentes induites (iPS-NPCs) peuvent représenter la source cellulaire autologue idéale pour la thérapie cellulaire visant à promouvoir la remyélinisation et la neuroprotection des maladies de la myéline. Jusqu'à présent, le potentiel thérapeutique de ces cellules a été abordé dans des conditions néonatales. Cependant, l'efficacité de la réparation et de la sécurité de ces cellules dans le système nerveux central (SNC), une condition associée à une diminution de la plasticité cellulaire et effarouchement, reste à être bien traités. D'ailleurs, il reste à démontrer si le comportement de ces cellules ressemble à celle des NPCs du SNC. D'abord, j'ai comparé des iPS-NPCs de souris avec des cellules embryonnaires du SNC, in vitro et après greffe dans des modèles de démyélinisation de la moelle épinière de souris adulte. Nos données ont révélé la capacité de survie, intégration, migration et différenciation rapide des cellules greffées en oligodendrocytes matures. Les cellules greffées ont généré de la myéline compacte autour des axones, la restauration de n¿uds de Ranvier et la vitesse de conduction aussi efficacement que les précurseurs du SNC dérivés tandis supplantant cellules endogènes. Ensuite, pour valider la fonctionnalité des précurseurs gliaux humains dérivés des iPS-NPC, je les ai transplantés dans des modèles nouveau-nés et adultes de dys/démyélinisation. Mes données ont montré la migration généralisée, l'intégration et génération de oligodendrocytes fonctionnels, la formation de la myéline compacte tout en reconstruisant n¿uds de Ranvier dans chez les nouveau-nés et les adultes greffés
Induced pluripotent stem cell-derived neural precursor cells (iPS-NPCs) may represent the ideal autologous cell source for cell-based therapy to promote remyelination and neuroprotection in myelin diseases and can serve as suitable tools to model myelin disorders or to test the potential of pharmacological compounds. So far the therapeutic potential of these cells was approached in neonatal conditions. However, the repair efficacy and safety of these cells in the demyelinated adult central nervous system (CNS), a condition associated with decreased cell plasticity and scaring, remains to be well addressed. Moreover, whether the therapeutic behavior of these pluripotent-derived cells resembles that of physiologically committed CNS-derived precursors remains elusive. First, I used mouse iPS-NPCs and compared them side-by-side to embryonic CNS-derived cells, in vitro and in vivo after engraftment in models of adult spinal cord demyelination. My data revealed the prominent capacity of survival, safe integration, migration and timely differentiation of the grafted cells into mature oligodendrocytes. Grafted cells generated compact myelin around host axons, restoring nodes of Ranvier and conduction velocity as efficiently as CNS-derived precursors while outcompeting endogenous cells. Second, to validate the functionality of human iPS-NPC-derived glial precursors, I transplanted them in newborn and adult models of dys/demyelination. My data showed widespread migration, integration and extensive generation of functional oligodendrocytes ensheathing host axons, forming compact myelin while reconstructing nodes of Ranvier both in newborn grafted and adult demyelination contexts

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26

Tegas, Antonio Vasile. "Finite element modeling of flow/compression-induced deformation of alginate scaffolds for bone tissue engineering." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amslaurea.unibo.it/10209/.

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Trauma or degenerative diseases such as osteonecrosis may determine bone loss whose recover is promised by a "tissue engineering“ approach. This strategy involves the use of stem cells, grown onboard of adequate biocompatible/bioreabsorbable hosting templates (usually defined as scaffolds) and cultured in specific dynamic environments afforded by differentiation-inducing actuators (usually defined as bioreactors) to produce implantable tissue constructs. The purpose of this thesis is to evaluate, by finite element modeling of flow/compression-induced deformation, alginate scaffolds intended for bone tissue engineering. This work was conducted at the Biomechanics Laboratory of the Institute of Biomedical and Neural Engineering of the Reykjavik University of Iceland. In this respect, Comsol Multiphysics 5.1 simulations were carried out to approximate the loads over alginate 3D matrices under perfusion, compression and perfusion+compression, when varyingalginate pore size and flow/compression regimen. The results of the simulations show that the shear forces in the matrix of the scaffold increase coherently with the increase in flow and load, and decrease with the increase of the pore size. Flow and load rates suggested for proper osteogenic cell differentiation are reported.

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27

Huang, Wen-Chin, and 黃文勤. "Study of Differences in Neural Differentiation between Mouse Embryonic Stem Cells and Induced Pluripotent Stem Cells." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/93079414896212544778.

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Анотація:

碩士
國立臺灣大學
解剖學暨生物細胞學研究所
99
Embryonic stem cells (ESCs) possess powerful ability to self-renew and to differentiate into all cell types of three germ layers. It has been reported that induced pluripotent stem cells (iPSCs) derived from somatic cells have been generated by transfecting four transcription factors including Oct4, Sox2, Klf4 and c-Myc. iPSCs provide advantages in various applications, such as developmental studies, pharmaceutical screening, and autologous cell transplantation. iPSCs have also showed powerful ability of self-renewal and differentiation into a variety of cell types and resemble the properties of ESCs. In this study, we compared the neural differentiation potency of mouse ESCs with that of iPSCs. We demonstrated the mouse ESCs and iPSCs generated neural stem/progenitor cells and various neural lineage cells in vitro with the neural inducer “retinoic acid (RA)” treatment. However, the differential expression of early neural genes between ESCs and iPSCs was observed by flow cytometry and quantitative PCR. Different developmental patterns were also observed during early and late stages of neural differentiation via immunocytochemistry. To test whether RA-Fgf/Erk pathway caused the differences in neural induction of ESCs and iPSCs, we used quantitative PCR to analyze gene expression of RA receptors and RA-metabolizing enzymes and performed Western blotting to assess the phosphorylation level of Erk1/2. We found that the RA receptors, RA-metabolizing enzymes and phosphorylation of Erk1/2 were expressed at significantly different levels between ESCs and iPSCs. Our results suggest that the neural differentiation potency of ESCs was observed higher than that of iPSCs, and the RA-Fgf/Erk pathway may play an important role in neural differentiation between ESCs and iPSCs.

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28

Huang, Hsin-Yi, and 黃欣儀. "Molecular Mechanism Undelying Urocortin-Induced Anti-Proliferation in Neural Stem Cells." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/11864528307599981665.

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博士
慈濟大學
醫學科學研究所
99
During corticogenesis, the proliferation and differentiation in neural stem cells are regulated precisely by a balance of extrinsic and intrinsic factors which direct progression into or exit from the cell cycle, and then determine the cortical cytoarchitecture. Urocortin (UCN), a member of the corticotrophin releasing hormone (CRH), is widely expressed in the adult brain and is involved in the functions of neuroprotection, stress response, immune suppression, and dendrite outgrowth. Although limited studies indicate UCN is expressed in the developing cortex, its expression and function are not clear in the embryonic brain. This investigation particularly examined the presence of UCN and its receptors in neural stem cells (NSCs) and clarified the mechanisms underlying the anti-proliferation effect of UCN in NSCs. This investigation demonstrated that UCN and its receptors CRHR1 and CRHR2 were present in (NSCs). During cortical development, the cortex expressed mRNA and protein from embryonic day 12.5 to postnatal day 1, implying that UCN might be involved in regulation of NSCs proliferation. Treatment of cultured NSCs with UCN reduced cell proliferation, self-renewal potential, growth fraction, and labeling index. The deceased labeling index was also observed in ex vivo cultured brain slice. Flow cytometry analysis revealed that UCN increased the population of NSCs arrested in G0/G1 phase. Ki67 staining for distinguishing these two phases demonstrated that UCN induced more NSCs stayed in G0 phase. This could be the consequence of cell cycle exit induced by UCN. In addition, UCN selectively increased the duration of G1 phase, resulting in prolonging cell cycle progression. Mechanistic studies in NSCs showed that UCN increased the expression of p21, leading to inactivation of CDK2, and ultmately hypophosphorylation of Rb. Interestingly, UCN directly inhibited histone deacetylase (HDAC) activity, resulting in histone hyperacetylation which transactivated expression of Krüppel-like factor 4 (Klf4) and p21. Knockdown of Klf4 resulted in downregulation of p21-mediated cell-cycling restriction caused by UCN. Furthermore, UCN upregulated p21 in NSCs, thus catalyzing their exit from the cell cycle. Results also showed that UCN promoted neuronal differentiation. These findings are consistent with a previous hypothesis, that lengthening G1 phase of NSCs promotes the switch from proliferation to differentiation, proposed by Calegari et al. These results suggest that UCN might be an anti-mitogen in developing cortex to regulate NSCs proliferation during corticogenesis.

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29

"Generation and characterization of induced neural cells from fibroblasts by defined factors." 2011. http://library.cuhk.edu.hk/record=b5894654.

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Анотація:

Tse, Chi Lok.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 116-131).
Abstracts in English and Chinese.
Declaration --- p.i
Abstract --- p.iii
Abstract in Chinese --- p.v
Acknowledgements --- p.vi
Table of Contents --- p.vii
List of Figures --- p.X
List of Tables --- p.xii
List of Abbreviations --- p.xiii
Chapter CHAPTER 1 --- General Introduction
Chapter 1.1 --- Regenerative Medicine --- p.1
Chapter 1.2 --- Embryonic Stem Cells and Reprogramming --- p.3
Chapter 1.3 --- Transdifferentiation --- p.6
Chapter 1.4 --- The Cerebellum --- p.7
Chapter 1.4.1 --- Functions of the cerebellum --- p.7
Chapter 1.4.2 --- Structure and organization of the cerebellum --- p.8
Chapter 1.4.3 --- Principle cellular components in the cerebellum --- p.12
Chapter 1.4.3.1 --- Purkinje cells --- p.12
Chapter 1.4.3.2 --- Granule cells --- p.12
Chapter 1.4.3.3 --- Mossy fibres --- p.13
Chapter 1.4.3.4 --- Climbing fibres --- p.13
Chapter 1.4.3.5 --- Deep cerebellar nuclei --- p.13
Chapter 1.4.3.6 --- Other cerebellar neurons --- p.14
Chapter 1.4.3.7 --- Neuroglia of the cerebellum --- p.16
Chapter 1.4.4 --- Circuitry of the cerebellum --- p.17
Chapter 1.5 --- Development of the Cerebellum --- p.21
Chapter 1.5.1 --- Anatomical changes during cerebellar development --- p.21
Chapter 1.5.2 --- Molecular control of cerebellar development --- p.25
Chapter 1.5.2.1 --- Specification of the cerebellar region --- p.25
Chapter 1.5.2.2 --- Neurogenesis from the ventricular zone --- p.26
Chapter 1.5.2.3 --- Neurogenesis from rhombic lip --- p.29
Chapter 1.6 --- Scope of the Thesis --- p.33
Chapter CHAPTER 2 --- Materials and General Methods
Chapter 2.1 --- Materials for Molecular Biological Work --- p.35
Chapter 2.1.1 --- Enzymes --- p.35
Chapter 2.1.2 --- Chemicals and others --- p.35
Chapter 2.1.3 --- Plasmid vectors and plasmid --- p.36
Chapter 2.1.4 --- Solutions and media --- p.36
Chapter 2.2 --- Materials for Tissue/Cell Culture --- p.38
Chapter 2.2.1 --- Chemicals --- p.38
Chapter 2.2.2 --- Culture media and solutions --- p.38
Chapter 2.2.3 --- Culture cells --- p.39
Chapter 2.3 --- Animals --- p.40
Chapter 2.4 --- Materials for Immunocytochemistry --- p.40
Chapter 2.5 --- Oligonucleotide Primers --- p.41
Chapter 2.6 --- RNA Extraction --- p.44
Chapter 2.7 --- Generation of cDNA from mRNA --- p.44
Chapter 2.8 --- Preparation of Recombinant Plasmid DNA --- p.45
Chapter 2.8.1 --- Small scale preparation of DNA --- p.45
Chapter 2.8.2 --- QLAGEN plasmid midiprep kit method --- p.46
Chapter 2.9 --- Preparation of Specific DNA Fragment from Agarose Gel --- p.46
Chapter 2.10 --- Subcloning of DNA Fragments --- p.47
Chapter 2.10.1 --- Preparation of cloning vectors --- p.47
Chapter 2.10.2 --- Subcloning of DNA fragment --- p.48
Chapter 2.10.3 --- Transformation of DNA into competent cells --- p.48
Chapter 2.11 --- Preparation of Competent Cells --- p.48
Chapter CHAPTER 3 --- Generation and Characterization of Induced Neurons
Chapter 3.1 --- Introduction --- p.50
Chapter 3.2 --- Experimental Procedures --- p.51
Chapter 3.2.1 --- Construction of expression vector --- p.51
Chapter 3.2.1.1 --- Preparation of insert DNA --- p.51
Chapter 3.2.1.2 --- Construction of entry vector --- p.52
Chapter 3.2.1.3 --- Construction of destination vector --- p.52
Chapter 3.2.1.4 --- Construction of expression vector --- p.52
Chapter 3.2.2 --- Generation of induced neural cells --- p.57
Chapter 3.2.2.1 --- Culture of mouse embryonic fibroblasts (MEF) --- p.57
Chapter 3.2.2.2 --- Production of expression vector containing retroviruses --- p.57
Chapter 3.2.2.3 --- Transfection and induction of neural fate of MEF --- p.57
Chapter 3.2.3 --- Immunocytochemcial analysis --- p.58
Chapter 3.2.4 --- Efficiency calculation --- p.59
Chapter 3.3 --- Results --- p.62
Chapter 3.3.1 --- A screen for cerebellar Purkinje and granule cell fate-inducing factors --- p.62
Chapter 3.3.2 --- Characterization of the induced neurons --- p.67
Chapter 3.3.2.1 --- Granule cell induction --- p.67
Chapter 3.3.2.2 --- Purkinje cell induction --- p.71
Chapter 3.4 --- Discussion --- p.102
Chapter 3.4.1 --- Roles of inducing factors in Purkinje cells and granule cells development --- p.102
Chapter 3.4.2 --- Mechanism of neural transdifferentiation --- p.107
Chapter CHAPTER 4 --- Future Directions
Chapter 4.1 --- Complete Induction of Purkinje Cell Fate --- p.111
Chapter 4.2 --- Induced Neurons of Different Subtypes --- p.112
Chapter 4.3 --- Mechanism of Transdifferentiation --- p.114
Chapter 4.4 --- Transdifferentiation and Regenerative Medicine --- p.114
Bibliography --- p.116

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30

De, la Vega Reyes Laura. "Novel techniques for engineering neural tissue using human induced pluripotent stem cells." Thesis, 2019. http://hdl.handle.net/1828/11427.

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Анотація:

Tissue engineering (TE) uses a combination of biomaterial scaffolds, cells, and drug delivery systems (DDS) to create tissues that resemble the human physiology. Such engineered tissues could be used to treat, repair, replace, and augment damaged tissues or organs, for disease modeling, and drug screening purposes. This work describes the development and use of novel strategies for engineering neural tissue using a combination of drug delivery systems (DDS), human induced pluripotent stem cells (hiPSCs), and bioprinting technologies for the generation of a drug screening tool to be used in the process of drug discovery and development. The DDS consisted of purmorphamine (puro) loaded microspheres that were fabricated using an oil-in-water single emulsion with 84% encapsulation efficiency and showed the slow release of puro for up to 46 days in vitro. Puro and retinoic acid (RA)-loaded microspheres were combined with hiPSCs-derived neural aggregates (NAs) that differentiated into neural tissues expressing βT-III and showed increased neural extension. hiPCS-derived neural progenitor cells (NPCs) were bioprinted on a layer-by-layer using a fibrin based-bioink and extrusion based- bioprinting. The bioprinted structures showed >81% cellular viability after 7 days of culture in vitro and the expression of the mature motor neuron (MN) markers HB9 and CHAT. Lastly, hiPCS-derived NPCs were bioprinted in combination with puro and RA-loaded microspheres and cultured for 45 days in vitro. The microspheres slowly released the drug and after 30 and 45 days the tissues contained mature neurons, astrocytes and oligodendrocytes expressing CHAT, GFAP, and O4, respectively. Changes in membrane potential indicated tissue responsiveness to different types of treatments such as acetylcholine and gamma-aminobutyric acid (GABA). In the future the bioprinted tissues could contain localized regions of varied drug releasing microspheres using a concentration gradient to promote differentiation into specific cell types in order to create more complex tissues. Moreover, these tissues will benefit from the presence of a neurovascular unit (NVU). Upon validation, the engineered tissues could be used as preclinical tools to test potential drugs and be used for personalized medicine by using patient specific hiPSCs.
Graduate
2020-11-19

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31

Lai, Chien-Cheng, and 賴建成. "Comparison of Neural Function of Normal Cells and Mucopolysaccharidosis Type II Cells Studied by Induced Pluripotent Stem Cells." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/50469578440109042692.

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32

Khadem, Mohtaram Nima. "Development of Multiscale Electrospun Scaffolds for Promoting Neural Differentiation of Induced Pluripotent Stem Cells." Thesis, 2014. http://hdl.handle.net/1828/5758.

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Анотація:

Electrospun biomaterial scaffolds can be engineered to support the neural differentiation of induced pluripotent stem cells. As electrospinning produces scaffolds consisting of nano or microfibers, these topographical features can be used as cues to direct stem cell differentiation. These nano and microscale scaffolds can also be used to deliver chemical cues, such as small molecules and growth factors, to direct the differentiation of induced pluripotent stem cells into neural phenotypes. Induced pluripotent stem cells can become any cell type found in the body, making them a powerful tool for engineering tissues. Therefore, a combination of an engineered biomaterial scaffold with induced pluripotent stem cells is a promising approach for neural tissue engineering applications. As detailed in this thesis, electrospun scaffolds support the neuronal differentiation of induced pluripotent stem cells through delivering the appropriate chemical cues and also presenting physical cues, specifically topography to enhance neuronal regeneration. This thesis seeks to evaluate the following topics: multifunctional electrospun scaffolds for promoting neuronal differentiation of induced pluripotent stem cells, neuronal differentiation of human induced pluripotent stem cells seeded on electrospun scaffolds with varied topographies, and controlled release of glial cell-derived neurotrophic factor from random and aligned electrospun nanofibers.
Graduate
nkhadem@uvic.ca

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33

BRAGA, ALICE. "TOWARDS A COMBINATION THERAPY FOR SPINAL CORD INJURY: PRNA-3WJ NANOTHERAPEUTICS AND TRANSPLANTATION OF INDUCED-NEURAL STEM CELLS." Doctoral thesis, 2017. http://hdl.handle.net/11562/965010.

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Анотація:

Spinal cord injury (SCI) is a debilitating pathology that has increased in prevalence over the last few decades. Despite improvements in modern medicine leading to a normal life expectancy, there are limited treatment options and still no fully restorative therapies. Several experimental therapies have been employed to ameliorate the hostile injured environment, amongst which stem cell transplantation is a standout. Neural stem cell (NSC) transplantation has shown promising results in promoting functional recovery in SCI models. However, major accessibility, ethical and immunocompatibility issues impede their clinical translation. These barriers can be overcome through the use of induced neural stem cells (iNSCs), obtained by direct reprogramming of autologous somatic cells, leading to the possibility of fully immunocompatible transplants. However, stem cell transplantations in pre-clinical models of SCI showed only limited CNS repair and protection, likely due to limited capacity of transplanted cells to robustly integrate in vivo. In this perspective, we envision that a combination of interventions aiming to first modulate the injured microenvironment will create a more hospitable context for the subsequent stem cell transplantation. Expression of Lipocalin 2 (Lcn2), a siderophore-binding protein implicated in modulation of inflammatory response in CNS diseases, is upregulated in reactive astrocytes that play a major role in inhibiting regeneration in SCI. We aim to ameliorate the deleterious injured environment through the downregulation of Lcn2 expression by delivering packaging RNA (pRNA) nanostructures to create a more amenable niche for improving the engraftment and differentiation of transplanted iNSCs. To achieve this, we first established a reproducible and reliable in vitro protocol for NPC- derived astrocyte differentiation, a more homogeneous population compared to primary astrocyte cultures, subsequently employed for safety and efficacy screening of pRNA nanostructures. NPC- derived astrocytes showed mature astrocytic phenotype after 15 days in vitro culture and gene expression changes upon activation, as observed in vivo. To silence Lcn2 expression we employed pRNA nanostructures, a bio-inspired construct and promising candidates amongst different nanotechnologies. Remarkably, pRNA transfection did not show any cytotoxicity on cultured astrocytes and we observed a specific and significant decrease in the expression of target mRNA upon pRNA transfection, i.e. reduction of classical hallmarks of activated astrocytes (GFAP and vimentin upregulation) here assayed as a proof of concept, and significant reduction in Lcn2 expression as a new therapeutic target. Finally, before combining pRNA transfection and iNSC transplantation in vivo, we first aimed to characterize and compare the therapeutic efficacy of transplanted iNSCs with the well-described NPCs in a murine contusion model of SCI. Preliminary data showed a similar survival rate after transplantation between iNSCs and NPCs and interestingly a similar trend in improvements of fine locomotor recovery 7 weeks after transplantation. Therefore, transplantation of fully immunocompatible iNSCs represents an innovative and promising therapeutic approach for SCI and in vitro results obtained from Lcn2 silencing showed encouraging results for a future promising combinatorial approach that aims at healing the injured environment and promoting functional recovery in SCI.

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34

BIDOLLARI, ERIS. "Neural stem cells differentiated from human induced pluripotent stem cells (iPSCs) as a novel in vitro model to study developmental pathways in Huntington Disease." Doctoral thesis, 2017. http://hdl.handle.net/11573/1058534.

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Huntington Disease (HD) is an autosomal dominant disorder characterized by motor, cognitive and behavioral features caused by a CAG expansion in the HTT (huntingtin) gene beyond 35 repeats. Since the discovery of the HTT mutation 24 years ago, more than 15,000 papers have been published on HD. However, both the role of the huntingtin (wtHTT) in healthy individuals and the molecular mechanisms by which the mutated huntingtin causes the disease remain unclear. The discovery of induced pluripotent stem cell (iPSC) technology offer the possibility to generate patient-specific iPS cells and to enable the development of in vitro HD models that more accurately reflect the human disease. The disease-specific iPSCs can be differentiated into relevant cell-types affected in HD, holding a great potential for disease modeling and drug screening. In the present study, we have obtained dermal fibroblasts from 16 HD patients and 6 healthy controls. Fibroblasts from a young adult healthy control, a young subject with 43 CAG repeats, in an early stage of the disease and two JHD (Juvenile Huntington disease) patients were reprogrammed into induced pluripotent stem cells. All iPS clones that show an uniform flat morphology are characterized for their stemness and pluripotency, both in vitro through embryoid bodies formation and in vivo through teratoma formation assay. iPS cells from a JHD (85CAG) and healthy control, were differentiated into neurospheres of neural precursors (NPCs) by a new protocol optimized for differentiation of iPSCs derived embryoid bodies expressing all the three germ layers (ectoderm, mesoderm and endoderm) in neurospheres of Neural Stem Cells (NSCs). Differentiation assay confirmed that they possessed the potentiality, to differentiate into subtypes of neuronal and glial cells. Gene expression profiling was performed on iPSC HD-derived neurospheres using GeneChip Human Transcriptome Array 2.0. iPSC HD-derived neurospheres exhibit an impaired brain development processes when compared with iPSC-derived neurospheres from healthy individuals. This study aimed to produce a valid model of the Huntington disease. This novel in vitro model will permit us to have a closer view to neuronal development networks by morphologically and physiological studies on the cell types obtained from the neuropheres of NPC.

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Lo, Wen-Cheng, and 羅文成. "Automatic Class Labeling of Human Induced Pluripotent Stem Cells in Microscopy Images using Convolutional Neural Networks." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/m5eaaz.

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碩士
中原大學
資訊工程研究所
107
This paper proposes an automatic class labeling system for human induced Pluripotent Stem cells (iPS cells) in microscopy images. The system uses a pre-trained convolutional neural network (CNN) classifier as the basis for classification, and produces color-coded images with class probabilities. There are a total of 4 classes, each of which represents the proliferation process of human iPS cells. The CNN used in our system consists of convolutional layers, max pooling, average pooling, and a fully connected layer, called iPSNet, was designed and evaluated using a training set of 30,000 images and a test set of 2,400 images. Our results demonstrated a relatively high accuracy (>95.5%) and short execution time, when compared with LeNet and AlexNet. In summary, our system could potentially be used as a tool to help biologists visualize the proliferation process of human iPS cells.

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36

Montgomery, Amy. "Combining induced pluripotent stem cells and fibrin matrices for spinal cord injury repair." Thesis, 2014. http://hdl.handle.net/1828/5272.

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Spinal cord injuries result in permanent loss of motor function, leaving those affected with long term physical and financial burdens. Strategies for spinal cord injury repair must overcome unique challenges due to scar tissue that seals off the injury site, preventing regeneration. Tissue engineering can address these challenges with scaffolds that serve as cell- and drug-delivery tools, replacing damaged tissue while simultaneously addressing the inhibitory environment on a biochemical level. To advance this approach, the choice of cells, biomaterial matrix, and drug delivery system must be investigated and evaluated. This research seeks to evaluate (1) the behaviour of murine induced pluripotent stem cells in previously characterized 3D fibrin matrices; (2) the 3D fibrin matrix as a platform to support the differentiation of human induced pluripotent stem cells; and (3) the ability of an affinity-based drug delivery system to control the release of emerging spinal cord injury therapeutic, heat shock protein 70 from fibrin scaffolds.
Graduate
0541
amy.lynn.montgomery@gmail.com

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37

Agbay, Andrew. "Development of guggulsterone-releasing microspheres for directing the differentiation of human induced pluripotent stem cells into neural phenotypes." Thesis, 2017. https://dspace.library.uvic.ca//handle/1828/8316.

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In the case of Parkinson’s disease, a common neurodegenerative disorder, the loss of motor function results from the selective degeneration of dopaminergic neurons (DNs) in the brain. Current treatments focus on pharmacological approaches that lose effectiveness over time and produce unwanted side effects. A more complete concept of rehabilitation to improve on current treatments requires the production of DNs to replace those that have been lost. Although pluripotent stem cells (PSCs) are a promising candidate for the source of these replacement neurons, current protocols for the terminal differentiation of DNs require a complicated cocktail of factors. Recently, a naturally occurring steroid called guggulsterone has been shown to be an effective terminal differentiator of DNs and can simplify the method for the production of such neurons. I therefore investigated the potential of long-term guggulsterone release from drug delivery particles in order to provide a proof of concept for producing DNs in a more economical and effective way. Throughout my study I was able to successfully encapsulate guggulsterone in Poly-ε-caprolactone (PCL)-based microspheres and I showed that the drug was capable of being released over 44 days in vitro. These guggulsterone-releasing microspheres were also successfully incorporated in human induced pluripotent stem cell (hiPSC)-derived neural aggregates (NAs), providing the foundation to continue investigating their effectiveness in producing functional and mature DNs. Together, these data suggest that guggulsterone delivery from microspheres may be a promising approach for improving the production of implantable DNs from hiPSCs.
Graduate

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38

"From Autopsy Donor to Stem Cell to Neuron (and Back Again): Cell Line Cohorts, IPSC Proof-of-Principle Studies, and Transcriptome Comparisons of In Vitro and In Vivo Neural Cells." Doctoral diss., 2013. http://hdl.handle.net/2286/R.I.18696.

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abstract: Induced pluripotent stem cells (iPSCs) are an intriguing approach for neurological disease modeling, because neural lineage-specific cell types that retain the donors' complex genetics can be established in vitro. The statistical power of these iPSC-based models, however, is dependent on accurate diagnoses of the somatic cell donors; unfortunately, many neurodegenerative diseases are commonly misdiagnosed in live human subjects. Postmortem histopathological examination of a donor's brain, combined with premortem clinical criteria, is often the most robust approach to correctly classify an individual as a disease-specific case or unaffected control. We describe the establishment of primary dermal fibroblasts cells lines from 28 autopsy donors. These fibroblasts were used to examine the proliferative effects of establishment protocol, tissue amount, biopsy site, and donor age. As proof-of-principle, iPSCs were generated from fibroblasts from a 75-year-old male, whole body donor, defined as an unaffected neurological control by both clinical and histopathological criteria. To our knowledge, this is the first study describing autopsy donor-derived somatic cells being used for iPSC generation and subsequent neural differentiation. This unique approach also enables us to compare iPSC-derived cell cultures to endogenous tissues from the same donor. We utilized RNA sequencing (RNA-Seq) to evaluate the transcriptional progression of in vitro-differentiated neural cells (over a timecourse of 0, 35, 70, 105 and 140 days), and compared this with donor-identical temporal lobe tissue. We observed in vitro progression towards the reference brain tissue, supported by (i) a significant increasing monotonic correlation between the days of our timecourse and the number of actively transcribed protein-coding genes and long intergenic non-coding RNAs (lincRNAs) (P < 0.05), consistent with the transcriptional complexity of the brain, (ii) an increase in CpG methylation after neural differentiation that resembled the epigenomic signature of the endogenous tissue, and (iii) a significant decreasing monotonic correlation between the days of our timecourse and the percent of in vitro to brain-tissue differences (P < 0.05) for tissue-specific protein-coding genes and all putative lincRNAs. These studies support the utility of autopsy donors' somatic cells for iPSC-based neurological disease models, and provide evidence that in vitro neural differentiation can result in physiologically progression.
Dissertation/Thesis
Ph.D. Molecular and Cellular Biology 2013

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39

Dubišová, Jana. "Léčba poranění míchy pomocí transplantace různých typů kmenových buněk." Master's thesis, 2015. http://www.nusl.cz/ntk/nusl-331126.

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Spinal cord injury (SCI) is complicated injury with serious socioeconomic consequences for the patient and his whole family. Big difficulty cause also extremely high living expenses for the patient with this type of injury. That's why there is a need for therapeutic methods which would help patients after SCI to recover the lost functions and be able at least partially to return to their normal life. Different therapeutic methods are being used for SCI treatment. In this study we used four various types of stem cells: human bone marrow stem cells (hBM-MSCs), human umbilical cord mesenchymal stem cells (hUC-MSCs), neural precursors derived from induced pluripotent stem cells (iPS-NPs) and neural stem cell line derived from human fetal spinal cord tissue (SPC-01). These cells have been transplanted intrathecally or intraspinally 7 days after induction of the experimental model of SCI in the rat. We studied expressions of genes related to neurogenesis, growth factors and inflammation 10 and 28 days after SCI. Our analysis showed significant changes in gene expression 10 days after SCI. Significant up-regulation in expression of vascular endothelial growth factor (Vegf), ciliary neurotrophic factor (Cntf) and interferon regulatory factor 5 (Irf5) were found after transplantation of hBM-MSCs and hUC-...

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40

Rybová, Jitka. "Patobiochemie lysosomálních střádavých onemocnění: studie Fabryho nemoci a příprava buněčných modelů X-vázaných chorob." Doctoral thesis, 2018. http://www.nusl.cz/ntk/nusl-388707.

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Human autopsy or biopsy tissue samples, mouse models and cell cultures of various types represent the most common materials in the investigation of cell pathogenesis of inherited diseases. This dissertation is devoted to all these approaches in the study of two X-linked lysosomal storage diseases, Fabry disease (FD,α-galactosidase A (AGAL) deficiency) and mucopolysaccharidosis type II (MPSII, idunorate-2- sulfatase (IDS) deficiency). The primary goal of the work was analysis of lipid blood group B antigens with terminal α-galactose (B-GSL) in the pancreas of FD patients with blood group B (FD-B).,In addition to the main glycosphingolipid (GSL) substrate, globotriaosylceramide (Gb3Cer), B-GSLs represent another minor substrate of AGAL. The deposition of undegraded B-GSL has been demonstrated in FD-B pancreas where it was significantly higher than in other organs such as the kidneys and lungs which accumulate mainly Gb3Cer. High concentration of lipid and non-lipid B-antigens was primarily confirmed in exocrine acinar epithelial cells of FD-B, accompanied by massive accumulation of ceroid (secondary sign of lysosomal storage). Unlike acini, the endocrine portion of the pancreas remained unaffected by accumulation of AGAL substrates. This interesting phenomenon of cell biology shows how a specific...

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41

Lin, Cheng-Yu, and 林政宇. "Convolutional Neural Networks with an Application on Human Induced Pluripotent Stem Cell Region Recognition Using Microscopy Images." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/92385542870545928601.

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Анотація:

碩士
中原大學
資訊工程研究所
105
We present a deep learning architecture Convolutional Neural Networks (CNNs) for automatic classification and recognition of reprogramming and reprogrammed human Induced Pluripotent Stem (iPS) cell regions in microscopy images. The differentiated cells that possibly undergo reprogramming to iPS cells can be detected by this method for screening reagents or culture conditions in iPS induction. The learning results demonstrate that our CNNs can achieve the Top-1 and Top-2 error rates of 5.9% and 0.9%, respectively, to produce probability maps for the automatic analysis. The implementation results show that this automatic method can successfully detect and localize the human iPS cell formation, thereby yield a potential tool for helping iPS cell culture.

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42

Chao, Che-Wei, and 趙哲瑋. "PartI: The effect of laminin surface - modified silica nanofiber scaffold on neural stem cell differentiationPartII: Neuroprotective effect of EGCG on LPS - induced Parkinson''s disease in rats." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/18176000070437979542.

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Анотація:

碩士
中原大學
奈米科技碩士學位學程
105
PartI: Electrospun fibrous scaffolds have been widely applied in tissue engineering. The objective of this study was developing aligned and random silica nanofiber scaffolds with and without laminin to evaluate the potential of rat neural stem cells (rNSCs) for neural differentiation. Herein, we used various methods such as trypan blue exclusion test, MTS assay, real-time polymerase chain reaction, and immunocytochemistry to evaluate the effects of the scaffolds on cell adhesion, cellular viability, and neuron-specific gene expression of the cells. The results show that the rNSCs cultivated on all groups of scaffolds were able to adhere. More importantly, fluorescence microscopy images illustrated that the scaffold with aligned 2-laminin (A2/L) fibers greatly increased the average neurite length and directed neurite extension of differentiated rNSCs along the fiber. Gene expression analysis demonstrated that the highest expression of neural-related genes, tuj1 was observed in rNSCs cultured on A2/L scaffolds. Other results indicated that the modification of laminin could enhance the glial differentiation of the rNSCs and it was independent of the fiber alignment. Based on the experimental results, the aligned nanofibrous silca scaffold with laminin could be used as a are superior candidates in neural tissue engineering. PartII: Parkinson’s disease (PD) is a common neurodegenerative disorder, which is characterized by the selective and progressive death of dopaminergic (DA) neurons in the substantia nigra. Increasing evidence suggests that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. (-)-Epigallocatechin-3-gallate (EGCG) is a major polyphenol in green tea, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. We Used liposome as a drug carrier, which can prolonged release of the EGCG. The aim of this study was to investigate the neuroprotective effect of liposome-VE-EGCG in a rat model of PD. Microglial activation and the injury of dopaminergic neurons were induced by LPS intranigral injection. Animal behavioral tests and biochemical assays were performed to evaluate the dopamine neuron degeneration and neuroprotective effects of liposome-VE-EGCG. Liposome-VE-EGCG significantly reduced amphetamine-induced rotational behavior in LPS-lesioned rats after 4 weeks. Furthermore, Liposome-VE-EGCG significantly decreased TNF-α levels, a marker of neuroinflammation in PD rats compared with saline group. These findings suggest that liposome-VE-EGCG exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and TNF-α.Thus EGCG represents a potent and useful neuroprotective agent for inflammation-mediated neurological disorders.

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