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MARCUZZO, STEFANIA. "New insights in the understanding of motor neuron disease by longitudinal brain and muscle MRI analysis and characterization of spinal cord-derived stem cells in G93-SOD1 mouse model of ALS." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/43854.
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Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disorder caused by the degeneration of motor neurons in the CNS, which results in complete paralysis of skeletal muscles. To establish the timeframe of motor neuron degeneration in relation to muscle atrophy in motor neuron disease, we have used MRI to monitor changes throughout disease in brain and skeletal muscle of G93A-SOD1 mice, a purported model of ALS. Longitudinal MRI examination of the same animals indicated that muscle volume in the G93A-SOD1 mice was significantly reduced from as early as week 8 of life, four weeks prior to clinical onset. Progressive muscle atrophy from week 8 onwards was confirmed by histological analysis. In contrast, brain MRI indicated that neurodegeneration occurs later in G93A-SOD1 mice, with hyperintensity MRI signals detected only at weeks 10-18. Neurodegenerative changes were observed only in the motor nuclei areas of the brainstem; MRI changes indicative of neurodegeneration were not detected in the motorcortex where first motor neurons originate, even at the late disease stage. This longitudinal MRI study establishes unequivocally that, in the experimental murine model of ALS, muscle degeneration occurs before any evidence of neurodegeneration and clinical signs, supporting the postulate that motor neuron disease can initiate from muscle damage and result from retrograde dying-back of the motor neurons.
In G93A-SOD1 ALS mice the response to neurodegeneration comprises proliferation and migration of ependymal stem progenitor cells (epSPCs), normally present and quiescent in spinal cord. We isolated epSPCs from G93A-SOD1 mice at 8 (asymptomatic) and 18 (symptomatic) weeks of age, and characterized the ability of epSPC cultures to proliferate and differentiate into the three neural cell lineages. G93A epSPCs produced neurospheres of self-renewing cells, and differentiated into more neurons and fewer astrocytes than control epSPCs, whereas oligodendrocytes did not show difference between the examined groups. The G93A-SOD1 neurons were small and the astrocytes were consistently activated. MicroRNA analysis revealed that miR-9 and miR-124a, involved in neural cell fate, were upregulated in differentiating G93A-SOD1 epSPCs, particularly at 18 weeks. miR-19a and miR-19b, implicated in cell-cycle regulation, were differentially expressed during epSPC differentiation in G93A-SOD1 compared with controls. Our findings demonstrated that G93A-SOD1 epSPCs have neurogenic potential constituting a source of multipotent cells useful for understanding the ALS pathogenesis and for identifying new therapeutic targets.
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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.
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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.
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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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Greenhowe, Jennifer. "Stem and progenitor cells in wound healing." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:87a9a7a1-b595-458a-913f-64497174f988.
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As more patients with large body surface area burns are surviving and requiring reconstructive surgery, there is a necessity for advances in the provision of bioengineered alternatives to autologous skin cover. The aims of this Thesis are to identify feasible source tissues of Endothelial Colony Forming Cells and Mesenchymal Stem/Stromal Cells for microvascular network formation in vitro with three-dimensional dermal substitute scaffolds. The working hypothesis is that pre-vascularised dermal scaffolds will result in better quality scarring when used with split thickness skin grafts. Human umbilical cord blood, peripheral blood and adipose tissue were collected and processed with ethical approval and informed consent. Samples were cultured to form endothelial outgrowth colonies and confluent Mesenchymal Stem/Stromal Cells, which were characterised using flow cytometry and expanded in vitro. Mesenchymal Stem/Stromal Cell multipotency was confirmed with tri-lineage mesenchymal differentiation. Primary cells were tested in a two-dimensional tubule formation co-culture assay and differences assessed using a proangiogenic antibody array. Tubule formation was tested in four different acellular dermal substitute scaffolds; Integra® Dermal Regeneration Template, Matriderm®, Neuskin-F® and De-cellularised Human Cadaveric Dermis. Umbilical cord blood was the most reliable source of Endothelial Colony Forming Cells, the yield of which could be predicted from placental weight. Microvasculature dissected free from adipose tissue was a reliable source of Mesenchymal Stem/Stromal Cells which supported significantly more tubule formation than Mesenchymal Stem/Stromal Cells from whole adipose tissue. Microvasculature Mesenchymal Stem/Stromal Cells secreted significantly higher levels of the proangiogenic hormone leptin, and addition of exogenous leptin to the tubule formation assay resulted in significantly increased tubule formation. Microvasculature was cultured in all four of the scaffolds tested, but depth of penetration was limited to 100µm. The artificial oxygen carrier perfluorocarbon was shown to increase two-dimensional tubule formation and may be useful in further three-dimensional scaffolds studies to improve microvascular penetration.
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Pearce, Daniel. "Intracellular analysis of stem and progenitor cells." Thesis, Kingston University, 2001. http://eprints.kingston.ac.uk/20685/.
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A population of rare pluripotential stem cells with extensive proliferative and self-renewal capabilities sustains haemopoiesis throughout life. Such cells, capable of differentiating into any haemopoietic lineage are required for gene therapy, ex-vivo expansion and stem cell transplantation strategies. It is currently not possible to positively identify these cells; their presence can only be retrospectively assessed through elaborate, time consuming culture techniques and animal repopulating studies. Stem cells can be isolated through negative selection, a complex and very expensive procedure. The CD34 antigen is routinely used as a surrogate marker of primitive haemopoietic cells and identifies most of the committed progenitors of the bone marrow as well as some of the more immature pluripotential cells. AC133, discovered in 1997, is reportedly expressed on a subset of CD34[sup]+stem/progenitor cells, suggesting an alternative for CD34. The present study first assessed the potential of one or both molecules (CD34/AC133) for progenitor cell acquisition in order to determine the status of AC133 as a unique stem cell antigen. Results suggested that selection of cells on the basis of AC133 excluded the more mature committed cells of the CD34[sup]+ population (especially erythroid). Consequently, the AC133[sup]+ population is more highly enriched (than the whole CD34[sup]+ cell population) for cells of a high proliferative potential and long-term culture initiating ability. The CD34 molecule can be very quickly upregulated. Upregulation is rapid (1 minute), independent of transcription/translation, and is unaffected by inhibitors of protein synthesis. Upregulation is of a fully formed glycosylated molecule and is probably from preformed intracellular stores. This research developed methodology for simultaneously fluorescent antibody-labelling internal and external stores of CD34. This was applied to investigating the internal expression of CD34, attempting to determine its significance in the hierarchy of haemopoietic cells, and this was achieved via flow cytometry, simultaneously examining the expression of internal CD34, external CD34 and one other established haemopoietic cell marker (CD38, AC133, Thy-1, CD164, CD117 and CD7). The results indicated that the CD34 molecule translocates from internal stores to membrane surface during external CD34[sup]+ haemopoietic stem/progenitor cell maturation and development. In addition, internal CD34 expression identifies a novel subset of primitive haemopoietic external CD34 negative (CD34[sup]NEG) cells, which may contain cells that precede external CD34[sup]+ cells in the hierarchy of haemopoiesis. Specific fluorescent antibody labelling was then confirmed by laser confocal microscope examination of labelled cells. The technique of simultaneously labelling 2 antigens for the confocal microscope was established, and allowed the cellular localisation of internal and external CD34 to be confirmed. A possible clinical application of this technology (internal CD34 labelling) to the monitoring of mobilisation protocols was further investigated by analysing daily peripheral blood samples, taken from patients undergoing G-CSF mobilisation therapy. Results suggested that cells with a more primitive phenotype (internal CD34[sup]+, external CD34[sup]NEG) than external CD34[sup]+ cells are released in significant numbers during the early stages of mobilisation, and are missed by the conventional harvest date. Such cells may have an improved transplant potential. This Ph.D. project has established the significance of internal CD34 expression a possible application and has identified a possible application for this technology.
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Chavez, Garcia Edison. "Phosphoinositides regulation and function in the ciliary compartment of Neural stem cells and Ependymal cells." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/221625.
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This thesis describes the work that I have carried out in the Laboratory of Neurophysiolgy at the Université Libre de Bruxelles, under the supervision of Prof. Serge Schiffmann, in collaboration with Prof. Stéphane Schurmans of Université of Liège.The work is divided in two distinct but related projects and the results section is thus divided into two main chapters. The results described are presented in the form of two manuscripts, the first chapter is named “Ciliary phosphoinositides regulation by INPP5E controls Shh signaling by allowing trafficking of Gpr161 in neural stem cells primary cilium”.The second is named “Regulation of phosphoinositides ciliary levels controls trafficking and ciliogenesis in ependymal cells”.Since both manuscripts are comprehensive regarding the results, and methods, these are inserted as such into the thesis.An expanded introduction to the field, placing the results into context, precedes these two chapters. An extended discussion section follows each chapter; it presents some elements of discussion not included in the manuscripts, the implications of the results and the scope for further research.Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Neilson, Kirstie Jane. "Differentiation of mouse embryonic stem cells into endothelial progenitor cells." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500200.
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Addicks, Gregory Charles. "Epigenetic Regulation of Muscle Stem and Progenitor Cells." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37112.
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Epigenetic mechanisms are of fundamental importance for resolving and maintaining cellular identity. The mechanisms regulating muscle stem and progenitor cell identity have ramifications for understanding all aspects of myogenesis. The epigenetic mechanisms regulating muscle stem cells are therefore important aspects for understanding the regulation of muscle regeneration and maintenance.
Important roles for the trithorax H3K4 histone methyltransferase (HMT) MLL1 have been established for early embryogenesis, and for hematopoietic and neural identity. Here, using a conditional Mll1 knockout (KO), we find that in vivo, MLL1 is necessary for efficient muscle regeneration, and for maintenance and proliferation of muscle stem and progenitor cells. Loss of Mll1 in cultured myoblasts reveals an essential role for expression of the myogenic specification gene Pax7.
Mll1 KO results in a minor decrease in Pax7 mRNA and a strong decrease of Pax7 protein. While MLL1 was found to bind the Pax7 promoter, Mll1 KO results in a minor decrease of H3K4me3 at Pax7, supporting a recognized non-HMT role for Mll1 at Pax7. Microarray analysis of mRNA expression in Mll1 KO myoblasts finds that Myf5 is the most strongly downregulated of all genes, unexpectedly, mRNA expression of previously identified MLL1 targets are unaffected by loss of MLL1 in myoblasts. Pax7 activates Myf5 expression through recruitment of a H3K4 HMT, and in Mll1 KO myoblasts expression of, and H3K4me3 at Myf5 is lost. Exogenous Pax7 rescues Myf5 expression and H3K4me3 at Myf5 in the absence of MLL1, indicating that Myf5 expression is conditional on Pax7, but not MLL1.
We also show that Myf5 DNA is methylated in non-myogenic cells, and in satellite stem cells that have never expressed Myf5, but is not methylated in satellite cells that are committed to the myogenic lineage, indicating that demethylation of Myf5 may be a fundamental step in myogenic commitment. Intriguingly, Myf5 promoter DNA becomes remethylated in Mll1 KO myoblasts.
This work finds that Pax7 expression and myogenic identity is partly dependent on MLL1 expression. Further, evidence is uncovered that myogenic commitment is initiated by demethylation of Myf5. These findings add to the understanding of the epigenetic mechanisms that regulate and define muscle stem cells.
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Schütte, Judith. "Analysis of regulatory networks in blood stem/progenitor cells." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648631.
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Ma, Kwai-yee Stephanie. "Identification and characterization of tumorigenic liver cancer stem/progenitor cells." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39557534.
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Liu, Yi. "LATEXIN’S ROLE IN REGULATING HEMATOPOIETIC STEM AND PROGENITOR CELLS." UKnowledge, 2013. http://uknowledge.uky.edu/physiology_etds/11.
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Previous studies in our lab identified a novel gene, latexin (Lxn), that regulates murine hematopoietic stem cells through balancing apoptosis, self-renewal and proliferation. In these dissertation studies, I performed a series of experiments to examine the function of Lxn using a Lxn conventional knockout mouse, and characterize Lxn’s role in the presence of hematopoietic stresses such as ionizing radiation, cytokines induced-mobilization, and hematopoietic malignancy.
The first series of experiments was designed to determine the role of Lxn in hematopoiesis under homeostatic conditions. I found that Lxn-/- mice exhibited hyperproliferative hematopoiesis, a repopulation advantage and elevated self-renewal capacity which was intrinsic to the Lxn-/- hematopoietic cells. Furthermore, I identified a reduction in apoptotic frequency in Lxn-/- hematopoietic progenitors, which may account for the expansion seen in the progenitor population.
In a second series of experiments, I discovered a role of Lxn in the radio-sensitivity of hematopoietic cells. I found that loss of Lxn in mice confers resistance to ionizing radiation. Lxn-/- mice showed rapid hematological recoveries after radiation exposure at the stem and progenitor cell (HSPC) level. The ablation of Lxn hindered irradiation-induced apoptosis which may underlie the radiation resistance through regulating hematopoietic recovery.
In a third series of experiments, I studied the interaction of Lxn-/- stem and progenitor cells with their microenvironment. Using a granulocyte colony-stimulating factor-induced mobilization model, I determined that the ability of HSPCs to mobilize into the bloodstream was significantly increased in Lxn-/- mice. The adhesive properties of hematopoietic cells were compromised in Lxn-/- animals. Gene expression studies on progenitor cells identified cell-to-ECM interactions were down-regulated upon Lxn deletion, implying the enhanced mobilization efficiency of hematopoietic cells from Lxn-/- mice correlated with reduced adhesion of hematopoietic progenitor cells to stroma.
Last, but not least, I performed a series of experiments to study the putative tumor suppressor role of Lxn in hematological malignancy. I found that Lxn expression was down-regulated in primary tumor and tumor cell lines by promoter methylation. Overexpression of Lxn inhibited lymphoma cell growth both in vitro and in vivo. Overexpressed Lxn increased apoptosis frequency by suppressing the expression of several anti-apoptotic genes, and therefore reduced the tumor growth.
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Prater, Michael David. "Progenitor and stem cell potential of mammary myoepithelial cells." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648364.
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Gu, P. "Isolation and characterization of porcine retinal stem/progenitor cells." Thesis, Queen's University Belfast, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437871.
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Giraddi, Rajashekharagouda. "Cell cycle kinetics of mammary stem and progenitor cells." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607789.
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Ulyanchanka, Sviatlana. "Identification of stem/progenitor cells in the postnatal thymus." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/11736.
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The thymus is the principal site of T-cell development and maturation. Failure to develop a functional thymus leads to severe immunodeficiency, while partially incorrect function of the organ can lead to a variety of autoimmune diseases as well as higher risk for infections and cancer. The thymus is organized into cortical and medullary regions, which are functionally distinct. The diverse array of thymic epithelial cells (TEC) are the key components of the thymic stroma, both the cortical and medullary TEC subsets are responsible for the establishment of a self-tolerant and self-restricted T-cell repertoire. The thymus is most active in young individuals, and undergoes a progressive naturally occurring involution from birth, which accelerates after puberty. Thymic involution is characterized by loss of thymus organization and function, including an overall reduction in the amount of functional thymic tissue. This results in decreased production of new naïve T-cells, and contributes to the diminished capacity of the aged immune system to adequately respond to new antigenic challenge. Involution of the thymus, both natural and in response to different therapies such as chemotherapy, raises interest in developing cell based treatment methods that will allow the restoration of the thymic architecture and so elevate immune reconstitution in vivo. The cellular mechanisms by which the postnatal thymus is maintained during homeostasis and involution are currently unknown. The earliest thymic progenitors in the thymus express Plet1; it has been established that from E12.5 to E15.5 these cells when purified are able to generate all thymic epithelial cell types and initiate thymus organogenesis. However, at least the latter capacity is reported to be lost from E18.5. A number of papers published provide evidence for the existence of both bipotent and unipotent TEC progenitors in the adult thymus. However the identity of these cells remains unknown, nor has the relationship between the mature and immature postnatal TEC compartments been established. The aim of my research was to investigate the cellular mechanism(s) that maintain the postnatal thymus. Specifically, I aimed to determine whether the thymus is maintained by a stem cell mechanism or by division of terminally differentiated thymic epithelial cells, and whether or not postnatal thymic epithelial stem/progenitor cells express functionally relevant levels of the transcription factor Foxn1. To address these aims, I used two approaches: in vivo genetically heritable lineage tracing and a novel grafting assay to assess the contribution of different lineages of TEC. This thesis describes the characterization of a novel mouse strain, the Foxn1CreERt2 line, which was predicted to allow conditional inducible manipulation of gene expression in TEC. I show that this deletor strain, while thymic epithelial cellspecific, could induce cre-mediated recombination in only in a low proportion of TEC and thus could not be used to address the initial aim of this work as described above. However, lineage tracing experiments using this line have provided evidence for a persistent cortical thymic epithelial progenitor/stem cell type, that was capable of rapid expansion within the cortical compartment over time. In parallel with characterisation of the Foxn1CreERt2 strain, I investigated the potential of various defined epithelial populations to contribute to the thymic environment in an assay of TEC potency. Using this technique I have established the potential of defined TEC subpopulations isolated from postnatal mice to generate cortical and medullary TEC. Among the populations analysed I have identified a minor TEC subset that can robustly contribute to both cortical and medullary TEC that coexpress Ly51 and Plet1. I have further shown, using a limiting dilution approach, that this population contains a postnatal common thymic epithelial stem/progenitor cells, present at a frequency of between 87.5 and 92.5 within this population. I have also produced evidence of a unipotent cortical progenitor population that is capable of long term expansion in vivo.
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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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Ma, Kwai-yee Stephanie, and 馬桂宜. "Identification and characterization of tumorigenic liver cancer stem/progenitor cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39557534.
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Li Ka Shing Prizes for best PhD theses in the Faculties of Dentistry, Engineering, Medicine and Science, 2006-2007published_or_final_version
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Pathology
Doctoral
Doctor of Philosophy
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Bird, Thomas Graham. "Liver regeneration by hepatic progenitor cells." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5634.
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The liver is the largest solid organ in the body and is frequently the site of injury. During disease, liver injury is usually compensated for by exceptionally efficient regeneration which occurs both from differentiated epithelia and also from an undifferentiated cell population with stem cell like qualities known as hepatic progenitor cells (HPCs). HPCs are particularly active during massive or chronic liver injury and therefore are an attractive target for much needed novel therapies to enhance regeneration in patients for whom the only current effective therapy is liver transplantation. Stem cells in other organs systems are believed to reside in a specialised microenvironment or niche which supports their maintenance and function. To investigate the hypothesis that HPCs are supported by a functional niche and are capable of regenerating hepatocytes, we commenced by establishing a number of murine in vivo models. Having shown a stereotypical niche, consisting of macrophages, myofibroblasts and laminin exists in both animal models and human disease, we investigated the active recruitment of extrahepatic cells into this niche and showed that macrophages are actively recruited from the bone marrow during liver injury. Macrophages were shown to influence HPC behaviour during injury. Furthermore using macrophages as a cellular therapy, induced HPC activation with corresponding changes to liver structure and function. Investigation of signalling pathways revealed and confirmed a TWEAK dependent activation of HPCs following macrophage transfer. Having demonstrated the potential for macrophage therapy via HPC activation, we aimed to study the ability of HPCs to regenerate the hepatic parenchyma. To do so we developed and characterised a novel model of hepatocellular injury and HPC activation. Using the genetic labeling of hepatocytes in this model we were able to show rapid and large scale repopulation of hepatocytes from a precursor source with HPCs being the critical precursor source of hepatocellular regeneration. In addition this process is again dependent on TWEAK signalling, without which HPC mediated regeneration fails resulting in mortality. Therefore HPCs are an attractive biological target for regenerative medicine, and both TWEAK signalling and autologous macrophage infusion offer genuine potential to manipulate these cells as future therapies.
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Jin, Xin. "Towards differentiation of mouse embryonic stem cells to thymic epithelial progenitor cells." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/12227.
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The thymus is the major site for T-cell generation and thus is important for the adaptive immune system. Development of a properly selected, functional T-cell repertoire relies on interactions between developing T cells and a series of functionally distinct thymic stroma cell types including the cortical and medullary thymic epithelial cells (TECs). The thymus is one of the first organs to degenerate in normal healthy ageing. Related to this, there is strong interest in developing protocols for improving thymus function in patients by cell replacement or regenerative therapies. Thymic epithelial progenitor cells (TEPCs) represent a potential source of cells for thymus transplantation. However, the only source of these cells for transplantation is currently fetal thymus tissue. If TEPCs could be generated from pluripotent cells, this could provide an alternative source of cells for transplantation. The work described in this thesis therefore had two central aims (i) to test the stability of thymic epithelial progenitor cells in vivo and (ii) to investigate the possibility of generating TEPCs or TECs from mouse embryonic stem (ES) cells. The forkhead transcription factor, Foxn1, is essential for the development of a functionally mature thymic epithelium, but is not necessary for formation of the thymic primordium or for medullary thymic epithelial sub-lineage specification. By reactivating Foxn1 expression postnatally in mice carrying a revertible hypomorphic allele of Foxn1, Foxn1R, I herein demonstrate that TEPCs that can express only low levels of Foxn1 mRNA can persist postnatally in the thymic rudiment in mice until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression. In parallel with this work, I confirmed the possibility of generating Foxn1-expressing cells from mouse ES cells by using a Foxn1 reporter cell line. As the thymic epithelium has a single origin in the third pharyngeal pouch (3pp) endoderm, I then tested whether or not TEPCs and /or TECs were generated during ES cell differentiation via existing protocols for generating anterior definitive endoderm differentiation cells from mouse ES cells. From this work, I showed that genes expressed in the 3pp and/or TEPC,-including Plet-1, Tbx1, Hoxa3 and Pax9, were induced by differentiation of ES cells using these protocols. I further showed that cells expressing both Plet-1, a marker of foregut endoderm and 3pp, and EpCAM, a marker of proliferating epithelial cells, were induced using a novel protocol (2i ADE) for generating ES cells from ADE. However, gene expression analysis and functional testing suggested that the majority of these cells were non-thymus lineage. I subsequently developed a novel protocol which combined this 2i ADE protocol with co-culturing of the differentiating ES cells with fetal thymic lobes, and demonstrated that this further induced 3pp and TEPC related genes. Finally, I modified the culture conditions in this protocol to conditions predicted to better support TEPC/TEC, and showed that in these conditions, the TEPC-specific markers Foxn1 and IL-7 were induced more strongly than in any other conditions tested. The data presented in this thesis therefore represent an advance towards an optimized protocol for successfully generating TEPCs from ES cells in vitro.
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Malandraki-Miller, Sophia. "Enhancing progenitor cells for cell therapy after myocardial infarction." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:205043f4-e3e0-4947-9afc-b43f1543e0bd.
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Based on data from the World Healthcare Organisation, cardiovascular diseases are the primary cause of disease-related death globally, with myocardial infarction (MI) being the most prevalent. If not treated effectively, MI can progress to heart failure (HF). With 70 million prescriptions for HF in 2014 and 515 people in the UK being hospitalised daily with MI, the British Heart Foundation calls for novel robust treatments. Even though cardiac stem cell (CSC) therapy for MI has been under investigation for more than a decade, there still has not been a consensus over the identity of the adult endogenous CSC. Recent clinical trials, using selected Ckit+ cells or the cardiosphere-derived cells (CDCs) have shown moderate results. The aim of this thesis was to develop a digestion-based method for isolation of cardiac progenitor cells (CPCs) from the mouse atria. The resulting "CTs" were isolated by collagenase/trypsin (where their name has resulted from) digestion with a prolonged period step for cell attachment. CTs were compared to isolated CDCs for their marker expression, using RT-PCR and Immunocytochemistry, showing cells with a mesenchymal phenotype which expressed SCA1 and CKIT. The CDCs had more of a fibroblast phenotype with higher Ddr2 and Wt1 expression. Using a TGF-β1 differentiation protocol, the CTs could be differentiated more effectively to a CM lineage than could the CDCs. In addition, Oleic acid (OA) supplementation stimulated the Peroxisome proliferator-activated receptor alpha pathway and led to maturation of the CT cells, both before and after differentiation. The differentiated CTs begin to express Tnnt2, while OA led to Myh7 increase and upregulated their oxidative metabolism. Finally, the CTs were more able to survive under serum-starvation than the CDCs, and transfection with miR-210 could enhance CT survival under these conditions and increased VEGF secretion. By digestion of the whole atria and allowing a prolonged time for attachment, we have developed a novel isolation protocol which generates a cell population containing a range of progenitors. Cells within this population can survive under serum starvation and can be differentiated to a CM lineage, making them a promising therapeutic population.
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Guzmán, Ramírez Natalia. "Characterization of stem/progenitor cells from human prostate cancer tissue." [S.l.] : [s.n.], 2009. http://www.zb.unibe.ch/download/eldiss/09guzmanramirez_n.pdf.
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Markeson, D. B. "Vascularised scaffolds for cutaneous wound reconstruction using stem/progenitor cells." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1469485/.
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The synthetic replacement of full thickness skin is suboptimal both aesthetically and functionally. One approach to improve existing dermal substitutes is to pre-vascularise them to facilitate incorporation. In so doing, the aim is to improve the trajectory of wound healing. More expeditious maturation has been suggested to improve outcomes. Endothelial colony forming cells (ECFCs), specialised progenitor cells required for vasculogenesis, were isolated from cord (CBECFC) and peripheral (PBECFC) blood. Mesenchymal stromal cells were separated from adipose tissue (AdMSCs). Using a proprietary device (μ-chemotaxis 3D), human umbilical vein endothelial cells, and CBECFC- and PBECFC-derived cells were compared for chemokinetic and chemotactic movement within collagen I gels, with or without fibronectin. PBECFC-derived cells migrated further than CBECFC-derived cells and HUVECs towards the chemoattractant. These data informed the fabrication of collagen I gels containing co-cultures of ECFC-derived cells with MSCs. An attempt was made to compress these gels to facilitate handling, but vascular tubule formation was not amenable to compression. HUVECs seeded as a monoculture within compressed gels also had a 100% mortality rate, although 62.5% AdMSCs and 66.4% human dermal fibroblasts survived the compression process. Since pre-formed tubules did not survive the compression process, various concentrations of ECFC-derived cells and MSCs were seeded within uncompressed collagen I gels in order to obtain an optimised vascular network. AdMSCs were compared to BMMSCs. PBECFC-derived cells were compared to CBECFC-derived cells and HUVECs. Optimised gels containing tubules formed by adult derived PBECFC-derived cells and AdMSCs were then scaled up and implanted into an in vivo immunodeficient mouse model. Host incorporation of the construct within this pre-vascularised gel was significantly improved compared to an empty gel control (p=0.04). In summary, it was possible to fabricate a pre-vascularised collagen I scaffold, using adult-derived stem/progenitor cells, increasing the rate of host incorporation in an in vivo murine model.
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Lu, Wei-Yu. "Defining the liver repopulating capacities of hepatic progenitor cells." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17875.
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The liver has the ability to regenerate rapidly during acute liver injury by activating mature hepatocytes to divide and restore the damaged liver mass. In contrast, the liver relies on hepatic progenitor cells (HPCs) which have the ability to differentiate into both hepatocytes and biliary cells for regeneration during chronic liver injuries. Whole organ transplant is the most effective treatment for end stage liver diseases. However, there is a constant shortage of donor organs causing the death of many patients while waiting for suitable donor organs. HPC transplant is a potential alternative for whole organ transplant. However the isolation of HPC which is scarce in the liver and the expansion of these cells to a number that is suitable for transplant have been challenging. To investigate the plausibility of using HPCs as an alternative for liver transplant, I developed a protocol to isolate and expand HPC in vitro. Using this system, I investigated the complex hierarchy of HPCs in aid to select a defined population of HPC that is suitable for transplant. I found the EpCAM+ CD24+ population marks a naïve population of HPC that might be suitable for cell therapy. I further investigate the liver repopulating capacities of these cells by isolating EpCAM+CD24+ HPC population by Fluorescence Activated Cell Sorting (FACS) from a hepatocellular injury model. Surprisingly, a subpopulation of the EpCAM+ CD24+ HPCs which are also CD133+ possesses a higher colony forming capacities has been identified. Most importantly, this population can be expanded to a large scale in vitro and able to repopulate the injured liver after transplant. This defined population of HPCs can also be isolated from a mouse model of fatty liver disease and the isolated HPCs can be expanded in vitro. These cells are able to repopulate the liver after cell transplantation. The presence of HPCs that are capable of being isolated from the fatty liver proved the potential of using HPCs for transplant in a clinical setting by using cells isolated human fatty liver that are from rejected for transplant to overcome the shortage of donor organs.
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Guthrie, Steven Mitchell. "Hemangioblasts from hematopoietic stem cells to endothelial progenitor cells and their effector molecules /." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010068.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 95 pages. Includes Vita. Includes bibliographical references.
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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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Chong, Tsz-yat Ian, and 莊子逸. "Inducing the progressive differentiation of hESCs into pancreatic progenitor cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196433.
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Diabetes is a chronic disorder of the pancreas, where a decline in the insulin-producing β-cell population disrupts metabolic homeostasis. Pancreatic transplantation has shown to be effective in circumventing the problem of β-cell insufficiency. However, availability of donor islets remains an obstacle. Although progressive differentiation of embryonic stem cells (ESCs) to pancreatic β-cells is a solution, current protocols are wrought with inefficiencies. It is obvious that to realize ESC differentiation for therapy many steps need to be optimized, and this study describes improvement of Pdx1+pancreatic progenitor derivation, a critical determinant of pancreatic fate.
The compounds melatonin and sPDZD2 have been suggested to act through the
Protein Kinase A (PKA) pathway to exert transcriptional effects, and in particular sPDZD2 stimulates the expression of pancreatic genes in INS-1E rat pancreatic cells. This led to the hypothesis that the PKA-targeting characteristics of said molecules could be exploited for pancreatic specification through post-translational activation ofPdx1. hESCs were first induced to form definitive endoderm before treatment with melatonin and sPDZD2. Pdx1 expression induced by these molecules was then compared with levels triggered by known pancreatic progenitor inducer Indolactam V (ILV). A secondary objective of this study was to assess the endoderm induction potential of small molecules in hESCs, which claim to be potentially useful in differentiation.
In this research, I show that small molecules are noticeably more challenging to use in the hESC context. Between the TGF-β pathwayactivatorsIDE-1 and 2, the latter is more potent at inducing endoderm formation, though it does not surpass the capabilities of Stauprimide, a molecule originally thought to only serve a priming purpose in mESCs.IDE-2 and Stauprimide consistently perform better than Activin A, the near universal factor for endoderm induction. Possible synergy between IDE-2 and Stauprimide was explored, but their combination appears detrimental to Sox17expression. Subsequent pancreatic differentiation was also inefficient, and my results affirm the immaturity of chemically-induced endoderm by contrasting with mainstream means of endoderm induction; levels of endoderm marker expression between the two methods are millions of folds apart. This work exposes the risks of using small molecules, and they necessitate proper characterization before being adopted for differentiation.
Most favorably, both sPDZD2 and melatonin were able to trigger Pdx1 expression in STEMDiffTm derived definitive endoderm; 10 and 30folds respectively, comparable to the known Pdx1 inducer ILV (25 folds). I also reveal concentration-mediated differentiation and proliferative purposes of ILV and sPDZD2, which are highly reminiscent of the signaling mechanisms involved during pancreatic development. Preliminary quantification of Pdx1+ cells suggest that high concentrations of ILV and sPDZD2 favor self-renewal of Pdx1+ progenitors, whilst lower doses elevate Pdx1 expression. Demonstration of Pdx1 at both gene and protein expression levels was encouraging, but it remains uncertain if melatonin and sPDZD2 manipulate PKA signaling to exert Pdx1 promoting effects. My work supports the use of melatonin as a candidate for pancreatic differentiation, and suggests involvement of sPDZD2 in deriving and expanding progenitors during pancreatic organogenesis.published_or_final_version
Biochemistry
Master
Master of Philosophy
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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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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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Redpath, Andia Nicole. "Pharmacological mobilisation of murine mesenchymal stem/progenitor cells : identifying potential mechanisms." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/50292.
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Mesenchymal stem/progenitor cells (MSPCs) isolated from adult tissues and expanded ex vivo exhibit multipotency, immunomodulatory and regenerative properties; and thus are currently being assessed in many clinical trials. In contrast, this study focuses on understanding native MSPC properties to ultimately exploit their regenerative potential using pharmacological methods. It was previously demonstrated that pretreatment of mice with VEGF over 4 days primed MSPCs for mobilisation from the bone marrow (BM) to the peripheral blood in response to the CXCR4 antagonist, AMD3100. In this study, possible mechanisms underlying this response were investigated. In order to examine the effect of VEGF on MSPCs an in vitro system was initially established. Furthermore, an in vivo approach was utilised to investigate the mechanism whereby mobilising factors prime MSPCs for mobilisation by AMD3100. Mesenchymal and haematopoietic stem/progenitor cell (HSPC) mobilisation were compared to give insight into whether common or distinct pathways are involved. Stem cells are actively retained in the BM due to their expression of CXCR4 and the constitutive expression of CXCL12. It was demonstrated in this study that AMD3100 stimulates HSPC and MSPC mobilisation by reversing the gradient of CXCL12, from the BM to the blood; an effect that could be blocked with a novel CXCL12 neutraligand. MSPCs in the BM are closely associated to tissue-resident macrophages, and through their interaction regulate retention of HSPCs. In this study, macrophage depletion induced mobilisation of HSPCs and significantly enhanced their mobilisation by AMD3100. In contrast, mobilisation of MSPCs was impaired; suggesting that mobilising factors may signal via macrophages to prime MSPCs. Similarly, mice pretreated with G-CSF – shown to also deplete macrophages – impaired pharmacological mobilisation of MSPCs. These results suggest that macrophages play opposing roles in regulating the mobilisation of HSPCs and MSPCs.
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Mooney, Ciarán James. "Expression of growth factor receptors by haematopoietic stem and progenitor cells." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7332/.
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The mechanisms that govern the lineage commitment of haematopoietic stem and progenitor cells (HSPCs) have been a topic of debate since the 1960s. Two models of lineage commitment have been described; a permissive model, in which haematopoietic growth factors (HGFs) stimulate proliferation and survival of distinct HSPC subpopulations to permit stochastic lineage-specification, and a deterministic model, which proposes that HGFs instruct HSPCs to differentiate towards a specific cell lineage. To provide further insight into whether HGFs provide instructive cues or act in a selective manner, this study has investigated the expression of fms-like tyrosine kinase 3 (Flt3), and the receptors for erythropoietin (EpoR) and macrophage-colony stimulating factor (M-CSFR) by single HSPCs within the bone marrow. Using single-cell qRT-PCR and flow cytometry, a large number of novel HSPC subpopulations have been identified based on receptor expression. Importantly, multiplex analysis of protein and mRNA expression revealed that the above receptors are rarely co-expressed during the early stages of haematopoiesis. Furthermore, Flt3 expression was identified within the haematopoietic stem cell compartment and in vitro analysis demonstrated that Flt3 ligand primarily acts on a subpopulation of downstream progenitors. These findings suggest that Flt3, EpoR and M-CSFR differentially regulate distinct early HSPC subpopulations.
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Dam, Noémie Thi Nhu Quynh. "Allogeneic cardiac stem/progenitor cells and innate immune and humoral responses." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC251.
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Dans une société vieillissante, les maladies cardiovasculaires comme l’infarctus du myocarde représentent un challenge pour le système de santé. Les cellules souches, qui ont le potentiel de régénérer/réparer les organes tout au long de notre vie, constituent un traitement thérapeutique prometteur. Les stratégies qui ont utilisé des cellules autologues se sont heurtées à des limites que n’ont pas les cellules allogéniques mais leur immunogénicité peut constituer un obstacle à leur utilisation. Notre objectif a été d’étudier l’interaction des cellules souches/progéniteurs cardiaques humaines (hCPC) avec le système immunitaire inné et humoral dans un contexte allogénique pour identifer les risques et/ou bénéfices d’une telle thérapie. Les résultats montrent que les hCPC sont faiblement susceptibles à la cytotoxicité des cellules NK et qu’elles peuvent moduler leur cytotoxicité et leur sécrétion de cytokines vers un profile antiinflammatoire. Au contraire, les hCPC peuvent être éliminées par CDC ou ADCC en présence de DSA-HLA-I mais pas de DSA-HLA-II. Les hCPC sont aussi capables de recruter des monocytes circulants. Elles peuvent promouvoir l’activation des monocytes ainsi que des macrophages M1 et M2a vers un profile anti-inflammatoire et immuno-régulateur. Elles orientent la différentiation de monocytes en cellules dendritiques vers un profile de macrophages anti-inflammatoires avec une fonction de présentation d’antigène réduite. En conclusion, les hCPC pourraient contribuer à la régulation de l’inflammation postinfarctus et à la régénération/réparation cardiaque en modulant l’activité des cellules immunitaires dans un contexte allogénique. Cependant, leur susceptibilité aux DSA-HLA pourrait nécessiter une sélection des donneurs pour éviter une rapide éliminationIn an aging society, cardiovascular diseases such as myocardial infarction represent a major challenge for the health system. Since stem cells have the potential to regenerate/repair the organs throughout our life, they offer an attractive and promising solution. Strategies using autologous cells have showed constraints that have lead to the development of allogeneic therapies, but the immunogenicity of allogeneic cells might constitute a major hurdle we need to address for their safe clinical translation. We sought to investigate the interaction of allogeneic human cardiac stem/progenitor cells (hCPC) with the innate and humoral immune systems to identify the risks and/or benefits of such therapy. Our studies revealed that hCPC are weakly susceptible to NK cell-mediated cytotoxicity. They have the capacity to modulate their cytotoxicity and to switch their secretion of cytokines towards an anti-inflammatory profile. In contrast, the presence of DSA-HLA-I but not DSA-HLA-II in recipient sera could induce the elimination of hCPC by CDC and ADCC. hCPC are able to recruit circulating monocytes and fine-tune their activation towards an anti-inflammatory regulatory profile. They promote the differentiation/activation of M1 and M2a macrophages into an anti-inflammatory/immuneregulatory profile. They could bend the differentiation of monocytes to dendritic cells towards anti-inflammatory macrophage-like cells with impaired antigen-presenting function. Overall, hCPC might contribute to the regulation of post-infarct inflammation and cardiac regeneration/repair by modulating the activities of innate immune cells in an allogeneic context. However, their sensitization to DSA-HLA requires a selection of the donors to avoid a rapid elimination
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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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PIBIRI, VALERIA. "Immunohistochemical markers of stem/progenitor cells in the developing human cerebellum." Doctoral thesis, Università degli Studi di Cagliari, 2018. http://hdl.handle.net/11584/255995.
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The aim of this study was to identify the stem/progenitor cell markers, by immunohistochemistry, in order to highlight the cortical neurogenesis niches during the different gestational ages. To this end, the following stem/progenitor cell markers have been utilized: Sox2, Pax6, Pax2, WT1, Nestin, Vimentin and Calretinin. The expression of these markers have been compared with the expression of those markers of mature neurons and glial markers including Neurofilament (NF), neuron specific enolase (NSE), Synaptophysin (Syn), Glial fibrillary acid protein (GFAP) and S100β.
Evaluating both stem/progenitor and mature cell markers lead to the identification of multiple stages of differentiation of neuronal and glial progenitors during gestation, in order to better understand the development of human cerebellar cortex.
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LAI, FEDERICA. "Immunohystochemical markers of stem/progenitor cells in the fetal human liver." Doctoral thesis, Università degli Studi di Cagliari, 2019. http://hdl.handle.net/11584/260751.
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The documentation and the characterization of human stem/progenitor cells of the liver is interesting subject of the current scientific literature. Stem/progenitor cells are a heterogenus population characterized by a range of morphological and immunohistochemical features from bile duct cells to hepatocytes. They are typically characterized by the self-renewal ability able to differentiate into diverse lineage after injury or damage.. This study evaluated the immunohistochemical expression of different type of cytokeratins (CK7, CK14 and CK19) at different gestational ages in order to identify stem/progenitor in fetal human liver. Objectives: The aim of this study was to identify the stem/progenitor cell markers, by immunohistochemistry, in order to highlight the immunoreactivity of CK7, CK14 and CK19 in human liver progenitor cells at different gestational ages. Material and Methods: Liver samples were obtained from 14 fetal liver from 7 to 38 weeks of gestation. Liver samples were formalin-fixed routinely processed and stained with with H&E for histology. Section were also immunostained with the following antibodies: anti-CK7, anti-CK14 and anti-CK19. Results: Cytokeratin 7 (CK7): From 7 to 12 weeks of gestation, the positivity for CK7 is evident in the cytoplasm of progenitor cells of hepatocytes. From 15 weeks to 19 weeks, its immunoreactivity is absent. At about 27 weeks up to 38 weeks, we have a moderate positivity than before. The bile ducts in the first 7 weeks of gestation are absent. From 15 weeks onwards, we have a strong positivity of CK7 in ductal cells, remaining until late gestational age. The positivity of CK7 in the bile ducts is cytoplasmic and perinuclear. Cytokeratin 14 (CK14): From 7 weeks to 12 weeks, a cytoplasmic positivity, mainly perinuclear, is present in the cytoplasm of progenitor cells. From 15 weeks to 19 weeks, no immunoreactivity was found in hepatoblasts. From 27 weeks up to 38 weeks, there is a positive recovery. On the other hand, there is no positive effect during the development of the ductal system. Cytokeratin 19 (CK19): From 7 to 12 weeks of gestation, we have an intense cytoplasmic positivity homogeneously spread at the level of progenitor cells. At 15 weeks it is more light and focal and then negativize and start again from 27 weeks. Like CK7, also the CK19 is intensely expressed in the bile ducts from 15 weeks and then maintained until the 38th gestational age studied. Conclusion: Immunohistochemistry with monoclonal anti-cytokeratin antibodies has revelated previously the presence of cytokeratins in embryonic and early fetal hapatocytes. With the differentiation of bile ducts at about the 10th week, cytokeratin, particulary CK19, disappears from liver cells but remains in bile duct cells. This study shows that the immunoreactivity of the analyzed cytokeratins, in particular CK7 and CK19, is well evident from the first weeks of gestation and is maintained even in late age.
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Sone, Masakatsu. "Different differentiation kinetics of vascular progenitor cells in primate and mouse embryonic stem cells." Kyoto University, 2004. http://hdl.handle.net/2433/147492.
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Gotoh, Shimpei. "Generation of Alveolar Epithelial Spheroids via Isolated Progenitor Cells from Human Pluripotent Stem Cells." Kyoto University, 2015. http://hdl.handle.net/2433/195967.
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Final publication is available at http://dx.doi.org/10.1016/j.stemcr.2014.07.005. Shimpei Gotoh, Isao Ito, Tadao Nagasaki, Yuki Yamamoto, Satoshi Konishi, Yohei Korogi, Hisako Matsumoto, Shigeo Muro, Toyohiro Hirai, Michinori Funato, Shin-Ichi Mae, Taro Toyoda, Aiko Sato-Otsubo, Seishi Ogawa, Kenji Osafune, Michiaki Mishima, Generation of Alveolar Epithelial Spheroids via Isolated Progenitor Cells from Human Pluripotent Stem Cells, Stem Cell Reports, Volume 3, Issue 3, 9 September 2014, Pages 394-403, ISSN 2213-6711.Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第18681号
医博第3953号
新制||医||1007(附属図書館)
31614
京都大学大学院医学研究科医学専攻
(主査)教授 妻木 範行, 教授 江藤 浩之, 教授 瀬原 淳子
学位規則第4条第1項該当
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Zhang, Yingying, and 张莹莹. "Functional ion channels in human bone marrow-derived mesenchymal stem cells and human cardiac c-kit+ progenitor cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B50567032.
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Baba, Shiro. "Flk1[+] cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model." Kyoto University, 2008. http://hdl.handle.net/2433/135803.
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Ewels, Philip Andrew. "Spatial organisation of proto-oncogenes in human haematopoietic progenitor cells." Thesis, University of Cambridge, 2013. https://www.repository.cam.ac.uk/handle/1810/245861.
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The eukaryotic cell nucleus is a highly organised organelle, with distinct specialised sub- compartments responsible for specific nuclear functions. Within the context of this functional framework, the genome is organised, allowing contact between specific genomic regions and sub-compartments. Previous work has shown that genes in both cis and trans can make specific contacts with each other. I hypothesise that such a preferred juxtaposition may impact the propensity for specific cancerinitiating chromosomal translocations to occur. In this thesis, I describe how I have extended and developed a ligation based proximity assay known as enriched 4C. I have coupled this technique with high throughput sequencing to determine genomic regions that spatially co-associate with the proto-oncogenes MLL, ABL1 and BCR. In addition to further developing the laboratory protocol, I have created bioinformatics tools used in the analysis of the sequencing data. I find that the association profiles of the three genes show strong correlation to the binding profile of RNA polymerase II and other active marks, suggesting that transcribed genes have a propensity to associate with other transcribed regions of the genome. Each gene also exhibits a unique repertoire of preferred associations with specific regions of the genome. Significantly, I find that the most frequent trans association of BCR is telomeric chromosome 9, encompassing its recurrent translocation partner gene ABL1. Interestingly, ABL1 is not at the maximum point of interaction. I use DNA-fluorescence in-situ hybridisation to validate the e4C association. My data supports a hypothesis that gene transcription has a direct role on genome organisation. I suggest that preferred co-associations of genes at transcription factories may promote the occurrence of specific chromosomal translocations.
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Gomes, Cátia Sofia Vicente. "Cues for cancer stem cells origin." Master's thesis, Faculdade de Ciências e Tecnologia, 2012. http://hdl.handle.net/10362/12439.
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Dissertação para obtenção do Grau de Mestre em
Genética Molecular e BiomedicinaNeural stem/progenitor cells (NSPC) can differentiate into neurons and glial cells in the central nervous system. Interestingly, NSPC biology is being applied to the study of human brain tumours, since these cells share some common features with glioma cells. However, it is not known the developmental stage with more similarities to glioma cells, or the most susceptible to malignant transformation. We aimed to identify the stage(s) in the NSPC differentiation process towards astrocytes where cells acquire phenotype characteristics comparable to glioma cells. NSPC that were obtained from E15 mouse brain, were grew as neurospheres (NS) and induced to astroglial differentiation until 7 days in vitro (DIV). After the cellular characterization of NS and differentiating cells, tumour-related factors were evaluated and their behavior compared to the one of GL261 mouse glioma cells. Astroglial differentiation led to a decrease in progenitor cells, as expected. Multidrug resistance-associated protein 1 expression decreased and autophagy marker increased with differentiation. The vascular endothelial growth factor (VEGF), matrix metalloproteinases and S100B protein increased until 2/3 DIV, while the 1 DIV cells showed the highest migratory potential towards the chemotactic VEGF or GL261-conditioned media. Comparison of data with glioma cells characteristics point to the first and second days of NSPC differentiation to astrocytes as the stages closing matching GL261 cells, and likely the most vulnerable to malignancy transformation.
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Xiang, Lina, and 向丽娜. "Functional characterization of human endometrial stem/progenitor cells in vitro and in vivo." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/206991.
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Human endometrium undergoes cyclic tissue breakdown and regeneration throughout a woman of reproductive life. It has been speculated that there is a subpopulation of stem/progenitor cells residing in the endometrium responsible to its remarkable capability. One key feature that distinguishes the adult stem cells is their quiescent state within the stem cell niche. Based on this unique stem cell property, slow-cycled cells from human endometrial tissues were examined and characterized.
The first aim of this study was to examine label retaining cells (LRCs) in long-term engrafted human endometrial tissues using a mouse xenotransplantation model in vivo. After various initial approaches, the maximum initial labeling of LRCs was determined and, only stromal LRCs were detected after a 12-week chase. Mesenchymal stem cell (MSCs) and stem cell-like phenotypic appearances were detected in a small proportion of stromal LRCs.
The second objective was to establish a novel method for identifying slow-cycled cells from cultivated endometrial epithelial and stromal cells in vitro. The method identified cells that retained fluorescence label after long-term culture. These cells were termed fluorescence retaining cells (FRCs). The variables and the different initial approaches leading to the establishment of the protocol for the identification of FRC were optimized.
The third objective further characterized the endometrial stromal FRCs. Endometrial stromal FRCs were enriched with cells having higher colony forming and self-renewal abilities when compared with non-FRCs. At subsequent passage (P2) the adult stem cell characteristics of cells derived from FRCs was more prominent and differentiated into mesenchymal lineages. Clonally derived stromal FRCs expressed higher self-renewal and pluripotent genes (BMI-1, NANGOG, OCT4, and SOX2). They also expressed endometrial mesenchymal stem cell phenotypic surface markers: CD146/PDGFRβ and W5C5, suggesting these cells might be of MSC origin.
The fourth objective was to examine the role of epithelial-stromal interactions on regulation of endometrial stem cells. Menstrual cycle day 2 epithelial conditioned medium significantly enhanced the colony forming ability of endometrial stromal cells. Protein expression analysis of the early menstrual phase conditioned medium showed two cytokines: angiogenin and interleukin 8, potentially involved in the regulation of endometrial stromal stem/progenitor cells.
The fifth objective was to examine the reconstitution ability of the endometrial clonogenic cells in vivo using a mouse xenotransplantation model. Endometrial clonogenic stromal cells together with epithelial cells reconstituted muscle-like tissue. Although no endometrial-like tissue was detected, the findings provide the first in vivo evidence that stromal stem/progenitor cells are present within clonogenic cells.
Overall, the thesis reports the existence of slow-cycled cells from human endometrium. By using various label retention techniques in vitro and in vivo a subpopulation of slow-cycled stromal cells which exhibit characteristics properties of adult stem cells was demonstrated for the first time.published_or_final_version
Obstetrics and Gynaecology
Doctoral
Doctor of Philosophy
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Masek, Lisa Christina. "The study of adhesive interactions between haemopoietic progenitor cells and bone marrow sinusoidal endothelial cells." Thesis, University of Southampton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242854.
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Kollek, Matthias [Verfasser], and Miriam [Akademischer Betreuer] Erlacher. "Improvement of hematopoietic stem cell transplantations by transient apoptosis inhibition in donor stem and progenitor cells." Freiburg : Universität, 2016. http://d-nb.info/1136263462/34.
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Sabapathy, S. "Optimisation of methods for the differentiation of human embryonic stem cells into retinal progenitor cells." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1459964/.
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Many ocular diseases result in visual impairment often leading to blindness with disease progression, one such example is Retinitis pigmentosa (RP). The underlying cause for blindness is often due to the degeneration of photoreceptors and supporting cells in the retina. Photoreceptors are responsible for the conversion of light signals into electrical impulses which are processed by the brain to form a visual image. Unlike other cells, photoreceptors cannot be regenerated by the body. For this reason current treatment for many ocular diseases aims to preserve what little vision patients hold. The only way such diseases could be cured is by regenerating photoreceptors and transplanting them into patients to replace lost cells and function. The differentiation of retinal cells from human embryonic stem cells (hESCs) is a difficult process. Current strategies produce low efficiencies of retinal cells which could not supply cells in a clinical environment. It is evident that the key lies within the tight control of the microenvironment of these cells at various stages of the differentiation process. In this study various optimisation avenues were investigated in order to increase the yield of retinal cells. By investigating the impact of various dissociation reagents and enzymes it was found that, the dissociation of cells using TrypLE Express significantly increased retinal gene expression. Using this reagent resulted in over a 100 fold increase in expression of photoreceptor precursor marker Nrl in comparison to the mechanical dissection with Collagenase IV (the control). In this investigation it was also found that the dissociation of cells during the process, in order to reduce cell densities is highly detrimental. The investigations were successful in finding some changes to the published protocols that optimised the differentiation process of pluripotent Shef3 hESCs into retinal cells.
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Brown, James Augustus. "Comparison of bone marrow mesenchymal stem cells and tendon progenitor cells cultured on collagen surfaces." Thesis, Virginia Tech, 2010. http://hdl.handle.net/10919/77011.
Full textAbstract:
Tendon injuries are a significant cause of morbidity in performance horses with superficial digital flexor tendon injury reported to represent up to 43% of overall Thoroughbred racehorse injuries. Natural repair is slow and results in inferior structural organization and biomechanical properties and, therefore, reinjury is common. The inability of tendon to regenerate after injury, or to heal with mechanical properties comparable to the original tissue, is likely attributable to low vascularity and cellularity of the tissue, low number of resident progenitor cells, and healing under weight-bearing conditions.
Strategies to improve tendon healing have focused on enhancing the metabolic response of tenocytes, modulating the organization of the newly synthesized extracellular matrix, or administering progenitor cells to enhance repair. Significant research effort has been directed at the use of adult mesenchymal stem cells as a source of progenitor cells for equine tendon repair and recent clinical applications have utilized adult autologous stem cells derived either from adipose tissue or bone marrow aspirates. Isolation of a homogenous population of stem cells from bone marrow is time-consuming, and there is much variation in cell numbers, cell viability and growth rates among samples. Recently, a population of progenitor cells has been isolated from equine flexor tendons, thus providing an alternative source of progenitor cells from the target tissue for therapeutic intervention.
The interaction between cells and the extracellular matrix (ECM) is an important factor in regulation of cell function. Proliferation, migration, differentiation and gene expression of many cell types are altered by adhesion to and interaction with matrix proteins and the extracellular environment. Tendon progenitor cells reside within a niche that comprises primarily parallel collagen fibers, and this niche plays an important role in regulating their function and differentiation. Culture conditions replicating this environment could be beneficial for both cell growth and matrix gene expression.
The objectives of the study were to compare cell growth kinetics and biosynthetic capabilities of bone marrow mesenchymal stem cells (BMMSCs) and tendon derived progenitor cells (TPCs) cultured on commercially available bovine, highly purified bovine, porcine, and rattus collagen sources and standard tissue culture surfaces. We hypothesized that collagen type I matrix would preferentially support TPC proliferation and up regulate gene expression for collagens and organizational components of tendon and therefore provide a culture system and progenitor cell type with advantages over the current practice of BMMSC expansion on standard cell culture plastic surfaces.
Cells were isolated from 6 young adult horses, expanded, and cultured on collagen-coated tissue culture plates, and no collagen control for 7 days. Samples were analyzed for cell number on days 4 and 7, and for mRNA expression of collagen type I, collagen type III, cartilage oligomeric matrix protein (COMP), and decorin on day 7. Glycosaminoglycan (GAG) synthesis was analyzed on day 7. Differences of cell number between collagen groups and cell type, and in gene expression and GAG synthesis between collagen groups and cell types, were evaluated by use of mixed-model repeated measures ANOVA. Pair-wise comparisons were made on significant differences identified with ANOVA using Tukey's post hoc test. Statistical significance was set at P<0.05.
A statistical significant (P=0.05) increase in cell number for TPCs grown on rattus collagen versus control on day 4 was observed. No difference in GAG synthesis or expression of collagen type I, collagen type III, COMP or decorin mRNA was observed between collagen groups and non-collagen controls for either cell type on day 7. TPCs cultured on all collagen types yielded more cells than similarly cultured BMMSCs on day 4, but only porcine collagen was superior on day 7. TPCs synthesized more GAG than BMMSCs when cultured on control surfaces only. BMMSCs expressed more collagen type I mRNA when cultured on control, porcine and highly-purified collagen, and more collagen type III when cultured on control, porcine, highly-purified collagen, and rattus collagen, than TPCs. Tendon-progenitor cells expressed significantly more COMP when cultured on control and all collagen types, and decorin when cultured on porcine, highly purified bovine and bovine collagen when compared to BMMSCs.
The results of this study revealed an advantage to culturing TPCs on randomly organized rattus collagen during the early growth phase. The beneficial effects of collagen-coated surfaces on cell proliferation is likely related to increased surface area for attachment and expansion provided by the random collagen matrix, and/or collagen-cell interactions. Tendon progenitor cells showed superior growth kinetics and expression of the matrix organizational components, COMP and decorin, than similarly cultured BMMSCs that expressed more collagen types III and I. TPCs synthesize more GAG compared to BMMSCs when cultured on plastic surfaces and there was no induction by collagen. Tendon progenitor cells should be considered as an alternative source of progenitor cells for injured equine tendons. Further in vitro studies characterizing factors that influence gene expression of both cell types is warranted.Master of Science
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Selander, Lars. "In vivo and in vitro approaches to induce beta cells from stem and progenitor cells." Doctoral thesis, Umeå : Umeå University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-25813.
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Xin, Xing. "Effects of polychlorinated biphenyls (PCBs) on telomere maintenance in hematopoietic stem cells and progenitor cells." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2026.
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Polychlorinated biphenyls (PCBs) are synthetic persistent organic compounds that are known to be carcinogenic to humans. Changes in telomerase activity and telomere length are hallmarks of aging and carcinogenesis. Retention of telomerase activity and long telomeres are key characteristics of stem cells and progenitor cells. I hypothesize that PCBs modulate telomerase activity and telomeres of hematopoietic stem cells and progenitor cells via interference of gene regulation and potentially disrupt cell differentiation. To investigate this possibility, I used progenitor-like cells, human promyelocytic leukemia cells (HL-60), and stem cells from rat bone marrow. I show that PCB126 and PCB153 display toxic effects on telomerase activity, telomere length and their related gene expression in progenitor-like HL-60 cells, but they did not exert much effect on differentiation. Further, an in vivo/in vitro study using rat bone marrow cells shows that PCB126-induced hematotoxicity, evidenced by reduction in telomerase activity and TERT gene expression, an increase of the differentiation and a change in the differentiation direction towards granulocytes, which indicate an effect on stem cell function. I also show that the most potent dioxin-like congener, PCB126, regulates hTERT gene expression by activation of the AhR pathway. Both AhR and ARNT work together as a repressor of hTERT transcription. This research improves our understanding of mechanisms of PCB126 and PCB153 toxicity on hematopoietic stem cells and progenitor cells, which will ultimately have significant implications for human health.
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Tabayoyong, William Borj. "Engraftment of embryonic stem cell-derived hematopoietic progenitor cells is regulated by natural killer cells." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1089.
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Embryonic stem (ES) cells possess the remarkable ability to form cells and tissues from all three germ layers, a characteristic known as pluripotency. In particular, the generation of ES cell-derived hematopoietic cells could serve as an alternate source of hematopoietic stem cells for transplantation in place of bone marrow cells, which are limited by donor availability and high immunogenicity. The advantages of ES cell-derived hematopoietic cells over bone marrow cells include a greater proliferative capacity, which alleviates the problems of donor shortage, and low level expression of MHC antigens, which suggests immune privilege. However, it is unclear whether the immune system is capable of recognizing and rejecting ES cell-derived hematopoietic cells following transplantation. The observation that ES cell-derivatives express low levels of MHC class I, the predominant inhibitory ligand for NK cells, led us to hypothesize that ES cell-derived hematopoietic progenitor cells (HPC) are susceptible to NK cell-mediated killing.
To test this hypothesis, we first generated HPCs from murine ES cells ectopically expressing HOXB4, a homeobox transcription factor that confers hematopoietic self-renewal, and confirmed that HPCs expressed low levels of MHC class I antigens. To specifically investigate the role of NK cells in regulating the in vivo engraftment of HPCs, we transplanted NK-replete Rag2-/- or NK-deficient Rag2-/-γc-/- mice with HPCs. We observed permanent HPC engraftment in Rag2-/-γc-/- mice; however, HPC engraftment was significantly reduced in Rag2-/- mice and was eventually eliminated over time. Bone marrow harvested from these animals showed that HPC-derived Lin-c-kit+ and Lin-Sca-1+ progenitor cells, critical progenitor cells for long-term hematopoietic engraftment, were deleted in Rag2-/- but not in Rag2-/-γc-/- mice.
Next, we focused on the mechanism of NK cell activation by HPCs. Increased expression of the cytotoxic proteins Granzyme B and Perforin in the NK cells of HPC-transplanted Rag2-/- mice confirmed in vivo NK cell activation. Phenotypic analysis of HPCs revealed high level expression of H60, a ligand of the NK activating receptor NKG2D, and neutralization of H60 rescued HPCs from NK cell-mediated killing.
Altogether, our results demonstrate that NK cells are a major barrier to the successful engraftment of ES cell-derived hematopoietic cells, underlining an important role of the innate immune system in regulating the long-term engraftment of ES cell derivatives.
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Kimura, Azuma. "Small molecule AT7867 proliferates PDX1-expressing pancreatic progenitor cells derived from human pluripotent stem cells." Kyoto University, 2019. http://hdl.handle.net/2433/242422.
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