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1
Huang, Hsuan-Ting. "Epigenetic Regulation of Hematopoiesis in Zebrafish". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10175.
Texto completo da fonteResumo:
The initiation of the hematopoietic program is orchestrated by key transcription factors that recruit chromatin regulators in order to activate or inhibit blood target gene expression. To generate a complete compendium of chromatin factors that establish the genetic code during developmental hematopoiesis, we conducted a large-scale reverse genetic screen targeting 425 chromatin factors in zebrafish and identified over 30 novel chromatin regulators that function at distinct steps of embryonic hematopoiesis. In vertebrates, developmental hematopoiesis occurs in two waves. During the first and primitive wave, mainly erythrocytes are produced, and we identified at least 15 chromatin factors that decrease or increase formation of \(scl^+\), \(gata1^+\), and \(\beta-globin e3^+\) erythroid progenitors. In the definitive wave, HSCs capable of self-renewal and differentiation into multiple lineages are induced, and we identified at least 18 chromatin factors that decrease or increase the formation of \(c-myb^+\) and \(runx1^+\) stem and progenitor cells in the aorta gonad mesonephros (AGM) region, without disruption of vascular development. The majority of the chromatin factors identified from the screen are involved in histone acetylation, histone methylation, and nucleosome remodeling, the same modifications that are hypothesized to have the most functional impact on the transcriptional status of a gene. Moreover, these factors can be mapped to subunits of chromatin complexes that modify these marks, such as HBO/HAT, HDAC/NuRD, SET1A/MLL, ISWI, and SWI/SNF. One of the strongest phenotypes identified from the screen came from knockdown of chromodomain helicase DNA binding domain 7 (chd7). Morpholino knockdown of chd7 resulted in increased primitive and definitive blood production from the induction of stem and progenitor cells to the differentiation of myeloid and erythroid lineages. This expansion of the blood lineage is cell autonomous as determined by blastula transplantation experiments. Though chromatin factors are believed to function broadly and are often expressed ubiquitously, the combined results of the screen and chd7 analysis show that individual factors have very tissue specific functions. These studies implicate chromatin factors as playing a major role in establishing the programs of gene expression for self-renewal and differentiation of hematopoietic cells.
2
Ullrich, Sebastian 1984. "Alternative mechanisms of gene regulation during hematopoiesis". Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/665801.
Texto completo da fonteResumo:
Gene regulation orchestrates the development of different cell types and organs from the same genetic blueprint. While the basic mode of gene regulation is driven by transcription factors, there are a variety of other mechanisms that determine the amount of RNA produced per genes. In this work we first investigate specifically intron retention as a mode of alternative splicing that alters the cellular transcriptomes. As a model, we use hematopoiesis. We compare intron retention in different stages of human and mouse B-cell development to granulocyte differentiation. We further explore expression and binding patterns of splicing regulatory factors. Second, we investigate the role of lncRNAs in the transdifferentiation of B-cell related lymphoma cells to macrophages. We specifically explore the role of a set of upregulated lncRNAs during this process. We deplete their expression during transdifferentiation with CRISPR/Cas9 to identify potential genes that retard or block the process and therefore are crucial for changing cell identity.La regulació gènica determina el desenvolupament dels diferents tipus cel·lulars, teixits i òrgans. Tot i que el mode bàsic de regulació és dirigit per factors de transcripció, existeixen una gran varietat de mecanismes que contribueixen a determinar la quantitat de RNA produïda pels gens. En aquest treball, investiguem en primer lloc la retenció d’introns com un tipus d’splicing alternatiu que altera el transcriptome cel·lular. Com a model biològic, ens centrem en la hematopoesi. Comparem la retenció d’introns en diferents estadis del desenvolupament de limfòcits B en humà i ratolí amb la retenció durant la diferenciació del granulòcits. Estudiem també el patró d’expressió i d’unió (binding) dels factors de regulació de l’splicing. En segon lloc, investiguem el paper dels RNA llargs no codificants (long non coding RNAs, lncRNAs) en la transdiferenciació de limfòcits B a macròfags. En particular, el paper d’aquells lncRNAs que son regulats positivament durant aquest procés. Reduïm la seva expressió durant la transdiferenciació mitjançant la tècnica CRISPR/Cas9 amb l’objectiu d’identificar gens amb el potencial de retardar o de bloquejar el procés i que, en conseqüència, pugui jugar un paper crucial en el canvi de la identitat cel·lular.
3
Durand, Ellen Marie. "Regulation of hematopoietic stem cell migration and function". Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11550.
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Hematopoietic stem cell transplantation (HSCT) is an effective treatment for blood disorders and autoimmune diseases. Following HSCT, these cells must successfully migrate to the marrow niche and replenish the blood system of the recipient. This process requires both non-cell and cell-autonomous regulation of hematopoietic stem and progenitor cells (HSPCs). A transgenic reporter line in zebrafish allowed the investigation of factors that regulate HSPC migration and function. To directly observe cells in their endogenous microenvironment, confocal live imaging was used to track runx1:GFP+ HSPCs as they arrive and lodge in the niche. A novel cellular interaction was observed that involves triggered remodeling of perivascular endothelial cells during niche formation. A chemical screen identified the TGF-beta pathway as a regulator of HSPC and niche interactions. Chemical manipulation of HSPCs was used to improve engraftment and repopulation capability following transplantation. Runx1:GFP fish treated with prostaglandin E2 (PGE2) during embryogenesis exhibit increased runx1+ cells in the AGM and CHT, consistent with previous in situ data. This increase in HSPCs is maintained into adulthood, even in the absence of prolonged PGE2 exposure. Kidney marrow from these treated fish can outcompete control marrow in transplantation assays. The ability of PGE2 to confer a long-term advantage on sorted mouse marrow populations in competitive transplantation assays was tested. I found that PGE2-treated short-term (ST)-HSCs, but not long-term (LT)-HSCs show enhanced transplantability in recipients compared to control animals. My studies demonstrate that the effects of PGE2 on HSC function persist over substantial time despite transient exposure. A population of short-term HSCs can engraft and give rise to long-term multilineage reconstitution following PGE2 treatment. Collectively, our studies have led to novel insights regarding the pathways involved in HSC migration, homing, and repopulation.
4
Martin, Richard. "Regulation of SCL expression and function in hematopoiesis". Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85582.
Texto completo da fonteResumo:
The development of the hematopoietic system occurs in two waves: a first wave of primitive erythropoiesis, which consists in the production of a single lineage, primitive erythrocytes, and a second wave of definitive hematopoiesis, which describes the generation of many specialized blood cell types from common hematopoietic stem cells. Whereas definitive hematopoiesis is fairly well understood, involves signals from the environment and the expression of lineage-specific transcription factors, the molecular mechanisms regulating primitive erythropoiesis remain to be defined. The aim of this thesis was to clarify the roles of the Stem Cell Leukemia (SCL) gene and Vascular Endothelial Growth Factor (VEGF) during primitive and definitive hematopoiesis. Although gene targeting experiments indicate essential roles for VEGF/Flk-1 signaling and SCL at the onset of hematopoiesis, their exact functions remain elusive. This work has revealed that different thresholds of VEGF are required for the migration of hematopoietic precursors from mesoderm to sites of hematopoiesis and for their subsequent expansion. Furthermore, it shows that SCL, a basic helix-loop-helix transcription factor, acts downstream of VEGF signaling to ensure the survival of primitive erythrocytes. During definitive hematopoiesis, conditional knock-out experiments establish a non-redundant role for SCL during erythroid and megakaryocytic differentiation. Yet, it remains unclear whether SCL is essential for commitment to these lineages. Results presented in this thesis suggest that SCL is not involved in commitment to these pathways, but rather acts to consolidate and expand the erythroid and megakaryocytic compartments, following lineage choice. Finally, despite the central role for SCL during hematopoietic development, the mechanisms regulating its tissue specific expression remain unknown. This work provides molecular and functional evidence that demonstrate that the homeodomain-Taken together, this work has elucidated molecular mechanisms which underlie cell fate decisions. It describes how the activity of a master regulator of erythroid differentiation, SCL, is regulated both by signals from the environment and at the transcriptional level, through combinatorial interactions between lineage-specific transcription factors.
5
Smith, Molly. "Alternative Splicing and Regulation of Innate Immune Mediators in Normal and Malignant Hematopoiesis". University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563527303459942.
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6
Gronthos, Stan. "Stromal precursor cells : purification and the development of bone tissue". Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phg8757.pdf.
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Bibliography: leaves 152-223. Experiments were designed to identify and purify human bone marrow stromal precursor cells by positive immunoselection, based on the cell surface expression of the VCAM-1 and STRO-1 antigens. The data presented demonstrates a hierarchy of bone cell development in vitro.
7
Gaboury, Louis A. "Studies of the role of mesenchymal cells in the regulation of hemopoiesis". Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28784.
Texto completo da fonteResumo:
Hemopoiesis is thought to be regulated in part by specific, but as yet undefined, interactions between primitive hemopoietic cells and fixed, non-hemopoietic marrow elements collectively referred to as the stroma. Recently, a marrow culture system has been described that allows the maintenance of primitive human hemopoietic progenitor cells for many weeks in the absence of exogenously added hemopoietic growth factors. The formation of a heterogeneous adherent layer in which many stromal elements are found appears to be important to the maintenance of hemopoiesis in this system. As part of the overall goal of delineating the cellular and molecular interactions involved, my first objective was to develop an experimental system for assessing the hemopoiesis-sustaining function of the adherent layer of long-term human marrow cultures. This required the identification of a suitable procedure for separating the hemopoietic and non-hemopoietic regulatory components so that the former could be used to quantitate the function of the latter. This was achieved using irradiation to selectively inactivate residual hemopoietic cells in long-term culture adherent layers, and using a medium containing cis-4-hydroxy-L-proline to selectively inactivate stromal cells and their precursors present in suspensions of unseparated human marrow which were then added back in co-culture experiments.
My second objective was to develop a strategy for obtaining purified populations of cells corresponding to the various mesenchymal cell types in long-term adherent layers. I therefore prepared a high titre SV-40 virus stock and used it to establish permanent, cloned lines from human marrow "fibroblast" colonies, long-term culture adherent layers, and umbilical cord endothelial cells. Characterization of the transformants generated showed that they were all positive for SV-40, and in general expressed the phenotypic characteristics of the cells originally infected. Functional studies showed that these transformants, like their normal counterparts, respond to activation by producing two types of hemopoietic growth factors.
These studies suggest that marrow mesenchymal cells may regulate the growth and maintenance of primitive hemopoietic cells by producing hemopoietic growth factors in response to appropriate perturbation. The availability of permanent cloned lines of human marrow stromal cells should facilitate future analysis of these events at the molecular level.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
8
Serbanovic-Canic, Jovana. "Using zebrafish to identify new regulators of haematopoiesis". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607950.
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Rothberg, Janet L. "Polycomb-like 2 (Mtf2/Pcl2) is Required for Epigenetic Regulation of Hematopoiesis". Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35323.
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Polycomb proteins are epigenetic regulators that are critical in mediating gene repression at critical stages during development. Core and accessory proteins make up the Polycomb Repressive Complex 2 (PRC2), which is responsible for trimethylation of lysine 27 on histone 3 (H3K27me3), leading to maintenance of chromatin compaction and sustained gene repression. Classically, Polycomb accessory proteins are often thought of as having minor roles in fine-tuning the repressive action of PRC2. Their actions have often been attributed to chromatin recognition, targeting to specific loci and enhancing methyltransferase activity. In our previous work in mouse embryonic stem cells (ESCs), we showed that Polycomb-like 2 (Mtf2/Pcl2) is critical for PRC2-mediated regulation of stem cell self-renewal through feed-forward control of the pluripotency network. In moving beyond the ESC model system, we sought to interrogate the role of Mtf2 in vivo by creating a gene-targeted knockout mouse model. Surprisingly, we discovered a tissue-specific role for Mtf2 in controlling erythroid maturation and hematopoietic stem cell self-renewal. Via its regulation of other PRC2 members, Mtf2 is critical for global H3K27me3 methylation at promoter-proximal sites in developing erythroblasts. Thus, Mtf2 is required for proper maturation of erythroblasts. Loss of Mtf2 also reduces HSC self-renewal leading to stem cell pool exhaustion. Additionally, misregulation of Mtf2 in leukemia models contributes to massive leukemic blast expansion at the expense of leukemic stem cell self-renewal. In the developing hematopoietic system, Mtf2 functions as a core complex member, controlling epigenetic regulation of self-renewal and maturation of both stem and committed cells.
10
Jarratt, Andrew. "Locus-wide studies into the transcriptional regulation of Runx1 in developmental hematopoiesis". Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572521.
Texto completo da fonteResumo:
Developmental hematopoiesis sees the generation of the first blood cells and definitive blood during embryonic development. The founding cell of definitive hematopoiesis, the hematopoietic stem cell (HSC), gives rise to all adult blood :I: ]] 1:: t '.1 '4 !..:. : 1 1 '.! . lineages throughout the the life span or an orgamism. It IS expected that future ex-vivo manipulation ofHSCs for therapeutic uses will benefit from a thorough understanding of the mechanisms, both cellular and genetic, that give rise to HSCs. One of the most critical regulators of HSC emergence in the embryo is the transcription factor (TF) Runxl. One aim of our lab is to decipher what controls the cis-regulation of Runxl to understand better how it exerts its function in the emergence of HSCs. In this thesis, chromatin assays were used to identify putative enhancers within the 1.3 Mb Runxl syntenic region. Seven novel enhancers were identified that mediate reporter gene expression in discrete patterns of Runx1-specific hematopoietic expression in transient transgenic embryos. Characterization of the cells marked by one of these enhancers, the + 11 0 enhancer in a transgenic mouse line, showed that it is active in clonogenic progenitors at Ell.5, but, interestingly, not HSCs. Finally, chromosome conformation capture (3C) assays showed physical interactions between the Runxl PI and P2 promoters and between the Runxl PI and P2 promoters and putative regulatory elements in the 1.3 Mb syntenic region. Together, these data increase our understanding of the complexity of Runxl cis-regulation during development and provide a starting point for characterizing what upstream trans-acting factors converge on Runxl to specify blood.
11
Junkunlo, Kingkamon. "Regulation of hematopoiesis in the freshwater crayfish, Pacifastacus leniusculus : role of transglutaminase". Doctoral thesis, Uppsala universitet, Jämförande fysiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-327921.
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The freshwater crayfish, Pacifastacus leniusculus, has been used as a model for studying hematopoiesis or blood cell production or hematopoiesis and immunity. The work of this thesis aims to investigate the impact of factors such as ROS signaling, Ast1, and the PVF/PVR signaling pathway in controlling stem cell behavior during hematopoiesis and specifically the role of the crosslinking enzyme transglutaminase (TGase) in regulation of hematopoiesis. The role of ROS in crayfish hematopoiesis was characterized by using the antioxidant named NAC to inhibit ROS production. Low ROS level resulted in a prolonged decrease in hemocyte numbers and a combined injection of LPS and NAC caused a slower rate of new hemocyte production. A low ROS level in cell cultures supplemented with crude Ast1 was found to inhibit cell spreading and a high extracellular TGase activity was detected on the surfaces of APC and HPT cells. We suggest that ROS serves as a prime signal to control proliferation and differentiation of progenitor cells by affecting extracellular TGase activity. We reported an inhibitory effect of Ast1 on TGase enzyme activity and on its crosslinking activity and consequently Ast1 affects the clot formation and thus coagulation by inhibiting the crosslinking activity of the TGase enzyme. Secretion of the clot protein (CP) and the production of CP filament network between spreading cells were observed in HPT cell cultures in vitro. In the presence of CP together with Ast1 in 3D-collagen-I cultures, HPT cells were found to be more elongated and they formed chains of cells throughout the surrounding matrix. In the HPT tissue, CP was located around the HPT cells or around the lobules of HPT, and thus, CP was demonstrated to be a part of ECM and to possibly function together with collagen in generating a suitable environment for HPT progenitor cells. The inhibition of PVF/PVR downstream signaling pathway by Sunitinib malate resulted in a dramatic change of cell morphology and induction of an increase cell surface area during cell culture. The addition of crude Ast1 into the cell cultures in vitro enhanced this effect. Consequently, cell migration was stimulated and a high extracellular TGase activity on HPT cell surface was found after this inhibition. In conclusion, the work in this thesis provides new insight in understanding the role of the extracellular matrix (ECM) and extracellular TGase activity in controlling stem cell activity.
12
Chiou, Chuang-Jiun. "Expression of Granulocyte-Macrophage Colony-Stimulating Factor Gene in Insect Cells by a Baculovirus Vector". Thesis, University of North Texas, 1989. https://digital.library.unt.edu/ark:/67531/metadc798471/.
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The focus of this research is to describe the production and characterization of the human granulocyte-macrophage colony-stimulating factor (hGM-CSF) in insect cells, using Autographa californica buclear polyhedrosis virus (AcNPV) as an expression vector. All three forms of biological activity of hGM-CSF. Following N-glycanase treatment, the two glycosylated hGM-CSF proteins (15.5 and 16.5 KDa) which bound to Concanavalin A affinity column ran as a 14.5-15.5 KDa band on SDS-PAGE. Western blot analysis of expression in Sf9 cells treated with tunicamycin revealed only the presence of the 14.5 KDa species. The N-terminal amino acid sequence of the recombinant hGM-CSF was identical to that of natural hGM-CSF deduced from cDNA. These results demonstrate that baculovirus-produced hGM-CSF could be N-glycosylated in Sf9 cells, the signal peptide of recombinant hGM-CSF could be recognized and cleaved by infected insect cells and the resultant molecule secreted into the medium.
13
Robinson, Simon N. "Proliferation regulation of haematopoietic stem cells in normal and leukaemic haematopoiesis". Thesis, University of St Andrews, 1992. http://hdl.handle.net/10023/14965.
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The cellular integrity of the blood is maintained by the cellular output of the haematopoietic stem cell population which produces the specialized precursors and differentiated cells which constitute the blood. The investigation of haematopoietic stem cell behaviour and regulation has been hampered by both the difficulty in their identification and the development of relevant assay systems. The purpose of this investigation was to study the behaviour and regulation of the haematopoietic stem cell population in normal and leukaemic haematopoiesis using an in vitro assay of a primitive haematopoietic precursor. The use of a combination of haematopoietic colony-stimulating factors [interleukin 3 (IL3)/multi-CSF and macrophage colony-stimulating factor (M-CSF/CSF-1)] in semi-solid agar culture of murine haematopoietic tissue, stimulated the proliferation of a haematopoietic colony-forming cell, defined as the "HPP-CFCIL3+CSF-1" population, which was characterized by a high proliferative potential, a multipotency and behavioural and regulatory properties consistent with its being a primitive haematopoietic precursor and possibly a component of the haematopoietic stem cell population. The proportion of the in vitro HPP-CFCIL3+csf-1 population in S-phase in normal murine marrow, was determined to be relatively low at approximately 10%, increasing to approximately 40% in sublethally X-irradiated, regenerating murine marrow and the respective presence of the haematopoietic stem cell proliferation inhibitor and stimulator was demonstrable by the induction of appropriate kinetic changes in the in vitro HPP-CFCIL3+CSF-1 population. In leukaemic haematopoiesis, leukaemic proliferation often occurs at the expense of apparently suppressed normal haematopoiesis. In vitro HPP-CFCIL3+CSF-1 assay of the haematopoietic stem cell proliferation regulators in a number of murine, myeloid leukaemic cell lines, failed to demonstrate either increased levels of the haematopoietic stem cell proliferation inhibitor, or evidence of a direct-acting, leukaemia- associated proliferation inhibitor, however, evidence of a leukaemia- associated impairment of inhibitor and stimulator production was observed and this may be a possible mechanism by which the leukaemic population develops a proliferative advantage over normal haematopoietic tissue. The identification of a possible mechanism of leukaemic progression and suppression of normal haematopoiesis may subsequently allow the development of potentially more effective disease treatment and management regimes. The endogenous haemoregulatory tetrapeptide: Acetyl-N-Ser- Asp-Lys-Pro [AcSDKP, Mr=487 amu] is reported to prevent the G0-G1 transition of haematopoietic stem cells into S-phase. The mechanism of action of AcSDKP and a number of related peptides, was investigated in relation to the stem cell proliferation stimulator and inhibitor. AcSDKP demonstrated no direct haemoregulatory role against the in vitro HPP-CFCIL3+CSF-1 population, which is consistent with reports that AcSDKP is not active against cells already in late G1, or S-phase, rather it appeared to act indirectly by impairing the capacity of the haematopoietic stem cell proliferation stimulator to increase the proportion of the in vitro HPP-CFCIL3+CSF-1 population in S-phase. An apparent impairment of stimulator action may explain the reported AcSDKP-associated 'block' of haematopoietic stem cell recruitment. A putative endogenous AcSDKP precursor and synthetic and degradative enzyme systems have been reported and the possible physiopathological role of AcSDKP in a number of myeloproliferative disorders has been implicated. The potential application of AcSDKP as a 'haemoprotective' agent administered prior to the use of S-phase- specific chemotherapy may be of clinical significance. The in vitro HPP-CFCIL3+CSF-1 assay of a primitive haematopoietic precursor cell population, which may be a component of the haematopoietic stem cell population, should play a significant role in the investigation of haematopoietic stem cell behaviour and regulation in both normal and aberrant haematopoiesis. With the characterization of the mechanism(s) of action of the haematopoietic stem cell proliferation inhibitor and stimulator and the haemoregulatory tetrapeptide AcSDKP, the manipulation of the haematopoietic system to clinical advantage can be envisaged, while the identification of the aberrant regulatory mechanism(s) in haematopoietic dysfunction may allow, the development of more effective disease treatment and management regimes.
14
Wang, Dennis Yi Qing. "Statistical modelling of gene regulation : applications to haematopoiesis". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607969.
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Maganti, Harinad. "Polycomb-like 2 (Mtf2/Pcl2) Mediated Epigenetic Regulation of Hematopoiesis and Refractory Leukemia". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37251.
Texto completo da fonteResumo:
The Polycomb Repressive Complex 2 (PRC2) epigenetically regulates gene expression by methylating lysine 27 on histone 3 (H3K27me3). While the role of PRC2 core members during hematopoiesis has been elucidated, the role of PRC2 accessory protein, Mtf2, has not been well characterized outside of mouse embryonic stem cells. To investigate the role of Mtf2 in vivo, we created a gene-targeted knockout mouse model. Using this model, we discovered that Mtf2 was a critical regulator of hematopoiesis and its loss within the hematopoietic cells leads to loss of global H3K27me3 levels at the transcriptional start sites (TSS) therefore leading to the overexpression of multiple signalling networks. These findings presented in the first part of my thesis place Mtf2 as a critical regulator of hematopoiesis and expand the role of Mtf2 beyond a canonical accessory PcG protein. While our murine studies revealed that the loss of Mtf2 did not cause leukemia in mice, our studies of MTF2 in human cells demonstrated that MTF2 deficiency within human Hematopoietic Stem and Progenitor Cells (HSPCs) causes a myelo-proliferative phenotype that is reminiscent of pre-leukemia. Furthermore, when we screened MTF2 expression within leukemic stem cell (LSC) enriched CD34+ CD38- cells isolated from primary Acute Myeloid Leukemia (AML) patient samples at diagnosis, we observed that MTF2 is miss-regulated in AML and its loss predicted refractory AML. Using MTF2 knockdown (KD) transcriptomic and ChIP-seq data, we drafted MTF2-PRC2 Gene Regulatory Network (GRN) in human HSPCs and LSC enriched cells. Finally, using the MTF2-PRC2 GRN, we uncovered a direct mechanism by which MTF2 regulates chemoresistance in AML and show that targeting this mechanism via MDM2 inhibitors sensitizes refractory AML to standard induction therapy. These findings presented in second part of my thesis demonstrate MTF2 as a novel prognostic marker for refractory AML and provide a novel therapy that helps target MTF2 deficient refractory AML.
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Haylock, David Norman. "Ex vivo expansion of human haemopoietic progenitor cells". Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phh4181.pdf.
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"December 2001." Includes bibliographical references (leaves 178-225) Focuses on the ex vivo growth of human haemopoietic progenitor cells with the objective of defining culture conditions for generating myeloid post-progenitor cells for therapy
17
Dong, Wei-Feng. "Expression and regulation of rhombotin-2 (RBTN/LMO-2) in normal hematopoiesis and leukemogenesis". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0017/NQ53807.pdf.
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Zannettino, Andrew Christopher William. "Molecular definition of stromal cell-stem cell interactions /". Title page, contents and summary only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phz32.pdf.
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Ma, Chun-hang. "Gene regulation of zebrafish hematopoiesis during embryonic development with special references to survivins and jak2a". Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41897249.
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Yates, Jeffrey Lynn. "THE GENETIC REGULATION OF THE RESPONSE OF HEMATOPOIETIC STEM/PROGENITOR CELLS TO THE CYTOSTATIC AGENT HYDROXYUREA". UKnowledge, 2006. http://uknowledge.uky.edu/gradschool_diss/420.
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Cellular proliferation is a key characteristic of hematopoietic stem and progenitor cells (HSC/HPCs) that allows for the production of all blood cell lineages during an individuals lifetime. While this feature of stem cells is strictly regulated during steadystate and stress hematopoiesis, it also contributes to the development of myeloproliferative disorders, such as chronic myelogenous leukemia, essential thrombocythemia, and polycythemia vera. It should come as no surprise then, that common treatments for these diseases often target the proliferative nature of the dysfunctional HSC/HPCs. Thus, the identification of molecular determinants of cell cycle regulation associated with these disorders could serve as targets for novel therapies. Using the hematopoietic system of the inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), it was found that the HSC/HPCs of the long-lived B6 mouse strain were less susceptible to the cytostatic agent hydroxyurea (HU) than the short-lived D2 mouse strain. A quantitative trait locus (QTL) analysis revealed a region of proximal chromosome 7 that regulates this response to HU. Congenic mouse strains were generated and phenotypic analysis confirmed that the B6 and D2 loci confer a low and high sensitivity of the HSC/HPCs to HU, respectively. We then showed that while this response of the HSC/HPCs to HU is independent of their cell cycle status, the B6 allele of this QTL confers a proliferative advantage to bone marrow cells after bone marrow transplantation. Having shown that proximal chromosome 7 regulates the response of HSC/HPCs to HU, we found it necessary to characterize the gene and protein expression profiles in order to identify the responsible candidate genes. We first analyzed mRNA expression profiles of HPCs from the parental and congenic mouse strains using gene microarrays and found that four genes within the congenic interval were differentially expressed. Real-time PCR confirmed that the expression profile of only one gene, Ndufa3, is significantly different in HPCs of B6 and D2 mice. Concurrently, we assessed the protein expression profiles of HPC-enriched mononuclear cells. Significant differences were found between the cytoplasmic and nuclear fractions of both strains, with a skewing of protein expression towards the D2 congenic strain.
21
Ma, Chun-hang, e 馬進恆. "Gene regulation of zebrafish hematopoiesis during embryonic development with special references to survivins and jak2a". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41897249.
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Varga, Andrea Erica. "Molecular characterisation, regulation and evolutionary analysis of uroplakin 1B : a tetraspanin family member /". Title page, errata, table of contents and summary only, 2003. http://hdl.handle.net/2440/37940.
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Uroplakin 1B (UPKIB) is an integral structural protein interacting with uroplakins 1A, 2 and 3 to form hexameric plaques along the bladder lumen in the asymmetric unit membrane of urothelial umbrella cells in humans and other mammals. UPKIB mRNA expression is deregulated in transitional cell carcinomas (TCCs), however the mechanisms of regulation of UPKIB have not been established. Using genome databases, a Xenopus UPKIB homologue was identified. Maximum Parsimony and BAMBE (Bayesian Analysis in Molecular Biology and Evolution) data support a close evolutionary relationship between mammalian and amphibian UPKIB mRNA. Using Unigene, UPKIB human expressed sequence tags were identified in tissues including brain, skeletal muscle and liver, suggesting the relatively widespread distribution of this membrane protein. The UPKIB genomic structure was also deduced using genome databases. Contig AC083800, identified in a high throughput genomic sequence database, spanned UPKIB and 9 exons and 8 introns were defined. A 67bp 5' untranslated region was identified using 5' rapid amplification of cDNA ends. This product was sequenced and a putative UPKIB promoter and transcription start site was deduced. Contig AC083800 spanned the transcription start site and putative promoter. Transcription factor binding motif prediction programs detected no TATA box, but did predict a CCAAT box and several binding motifs including 4 Sp-1 sites and a NFKB site. A weak CpG island was identified within a 0.5kb region including the putative promoter, exon 1 and intron 1, which was 54% GC rich with CpG:GpC ratio of 0.46, containing 15 CpG dinucleotides. Seven TCC cell lines and five peripheral blood lymphocyte samples were analysed for UPKIB expression using RT-PCR and two cell lines expressed UPKIB transcripts. Eleven CpG sites in the putative promoter were investigated for methylation using bisulfite modification analysis in normal PBL, TCC cell lines and patient TCC samples. An inverse correlation was established in TCC cell lines between UPKIB mRNA expression and degree of methylation. 5-Aza-2'deoxycytidine induced UPKIB mRNA expression in T24 cells, previously observed not to express UPKIB. Sequence analysis of patient samples revealed more complex CpG methylation patterns, reflecting tumour heterogeneity. In summary, the uroplakin 1B gene has been characterised and one mechanism of regulation of gene expression involves methylation.Thesis (Ph.D.)--Dept of Surgery, 2003.
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Gilmore, William Samuel. "A study of molecules involved in the regulation of the growth of haematopoietic cells and heart muscle cells in culture". Thesis, University of St Andrews, 1986. http://hdl.handle.net/10023/14970.
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The description of the molecular events responsible for the control of cell division and differentiation is, currently, one of the major goals of molecular and cellular biologists. Cell and tissue culture techniques have proved to be promising laboratory tools for the study of the regulators of cellular growth and differentiation. Most cells in culture require specific polypeptide growth factors which are supplied by the addition of a complex biological fluid such as serum or, in some instances, by the cells themselves. These growth factors usually act on their target cell via a membrane receptor to which they bind. The events which occur after the growth factor binds to the membrane receptor have not been fully described, but the phosphorylation of tyrosine residues in certain proteins has been observed. A study was made of the polypeptide growth factors responsible for the growth and differentiation of haematopoietic cells in vitro. These growth factors, called colony - stimulating factors (C.S.F.'s) were prepared from human placental conditioned medium, giant cell tumour conditioned medium and pokeweed mitogen stimulated spleen conditioned medium. A C.S.F. from human placental conditioned medium was radioiodinated and the binding of the labelled growth factor to an anti-C.S.F. antiserum was studied. The binding studies indicated that a purer C.S.F. preparation and/or a more specific antiserum was necessary in order to establish a radioimmunoassay for C.S.F. The C.S.F.'s from giant cell tumour conditioned medium were purified by ultrafiltration, hydrophobic - interaction chromatography, gel filtration and thiolpropyl - sepharose 6B chromatography. Two peaks of biological activity were observed on gel filtration. One of these peaks gave an apparent MW of 63,000 and the other peak gave an apparent MW of 30,200. The C.S.F. from pokeweed mitogen stimulated spleen conditioned medium was labelled with peroxidase and the binding of the labelled-C.S.F. to bone marrow cell membranes studied. The labelled-C.S.F. bound to the membranes and the binding exhibited a linear relationship with membrane protein content. Also a defined growth medium for chick embryonic heart cells was developed. These cells were observed to differentiate from primitive foetal cells into mature "adult-type" cells. The cells grew as a monolayer, had spontaneous activity and were seen to beat.
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Deng, Ruixia, e 邓瑞霞. "Astragaloside IV promotes haematopoiesis and enhances cytokines release by mesenchymal stromal cells mediated immune regulation". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/198839.
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Although tremendous efforts have been made to search for other novel growth factors in promoting marrow recovery after irradiation or chemotherapy, there have not been any efficient and safe agents discovered so far. Danggui Buxue Tang (當歸補血湯) as a traditional Chinese herbal decoction, is commonly used for replenishing blood loss in menstruating women, or enhancing erythropoiesis and immune responses in various settings. Our previous study confirmed that Danggui Buxue Tang promotes haematopoiesis and thrombopoiesis both in vitro & in vivo. Recent studies also showed that parenteral Astragalus regulates haematopoiesis in myelosuppressed mice and has protection effect on UV irradiated human dermal fibroblasts. However, astragaloside IV, as the major component of Astragalus, the "Monarch" (君葯) in Danggui Buxue Tang, the bioactivity and its possible mechanism on haematopoiesis remains unclear.
My studies showed that astragaloside IV had promoting effect on different lineages of haematopoietic CFUs forming including erythrocytes, granulocytes, monocytes and megakaryocytes both in normal and irradiated mice. In the K562 and CHRF apoptotic model, astragaloside IV exerted proliferation effect and induced K562 into megakaryocytic differentiation. Astragaloside IV up-regulated phosphorylation of ERK and it was abolished by PD98059. Meanwhile, astragaloside IV increased phosphorylated ERK migration into nuclei which enhanced cell survival and differentiation. EGFR inhibitor also attenuated the enhancing effect of astragaloside IV on ERK phosphorylation. It suggested that astragaloside IV is likely to function through EGFR with subsequent activation of ERK1/2 pathway. Furthermore, astragaloside IV also increased Bcl-2/Bax ratio by up-regulating Bcl-2 alone.
Bone marrow derived mesenchymal stromal cells are the major supporting cells involved in the haematopoietic microenvironment. My studies demonstrated that astragaloside IV also indirectly enhanced haematopoiesis by stimulating cytokine release from MSCs, especially IL-6, IL-8, MCP-1 and GRO1. I also found that matured and activated population of neutrophils was increased after cultured with mesenchymal stromal cells conditional medium stimulated by astragaloside IV. This finding further supported why there was a significant increment of CFU-GM in vitro culture with murine bone marrow collected from mouse model after astragaloside IV treatment, where MSCs serve as the feeder layer in such system in mice.
In conclusion, my studies explored the directly and indirectly dynamic and multiple targeted function of astragaloside IV on haematopoiesis. In addition to activating haematopoietic cells, astragaloside IV also stimulated mesenchymal stromal cells to secret cytokines that could modulate haematopoiesis and up-regulated neutrophil production and maturation. It provided a holistic view on how astragaloside IV induced synergistic effect on haematopoietic cells and mesenchymal stromal cells in the marrow microenvironment.published_or_final_version
Chinese Medicine
Doctoral
Doctor of Philosophy
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An, Ningfei, Bo Cen, Houjian Cai, Jin H. Song, Andrew Kraft e Yubin Kang. "Pim1 kinase regulates c-Kit gene translation". BIOMED CENTRAL LTD, 2016. http://hdl.handle.net/10150/622957.
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Background: Receptor tyrosine kinase, c-Kit (CD117) plays a pivotal role in the maintenance and expansion of hematopoietic stem/progenitor cells (HSPCs). Additionally, over-expression and/or mutational activation of c-Kit have been implicated in numerous malignant diseases including acute myeloid leukemia. However, the translational regulation of c-Kit expression remains largely unknown. Methods and results: We demonstrated that loss of Pim1 led to specific down-regulation of c-Kit expression in HSPCs of Pim1(-/-)mice and Pim1(-/-)2(-/-)3(-/-) triple knockout (TKO) mice, and resulted in attenuated ERK and STAT3 signaling in response to stimulation with stem cell factor. Transduction of c-Kit restored the defects in colony forming capacity seen in HSPCs from Pim1 (-/-) and TKO mice. Pharmacologic inhibition and genetic modification studies using human megakaryoblastic leukemia cells confirmed the regulation of c-Kit expression by Pim1 kinase: i.e., Pim1-specific shRNA knockdown down-regulated the expression of c-Kit whereas overexpression of Pim1 up-regulated the expression of c-Kit. Mechanistically, inhibition or knockout of Pim1 kinase did not affect the transcription of c-Kit gene. Pim1 kinase enhanced c-Kit S-35 methionine labeling and increased the incorporation of c-Kit mRNAs into the polysomes and monosomes, demonstrating that Pim1 kinase regulates c-Kit expression at the translational level. Conclusions: Our study provides the first evidence that Pim1 regulates c-Kit gene translation and has important implications in hematopoietic stem cell transplantation and cancer treatment.
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Chen, Aichun. "Regulation of lozenge transcription factor activity and blood cell development by MLF and its partner DnaJ-1". Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30064/document.
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L'hématopoïèse est le processus de formation des cellules sanguines différenciées à partir de cellules souches hématopoïétiques. Ce processus est étroitement contrôlé par l'intégration de signaux de développementaux et homéostatiques pour assurer une production équilibrée des différents types de cellules sanguines. Au niveau moléculaire, la régulation de ce processus est médiée par un certain nombre de facteurs de transcription, en particulier par les membres de la famille RUNX. Ainsi, des mutations affectant les membres de cette famille peuvent entrainer une déréglementation du programme de différenciation hématopoïétique et causer des hémopathies, dont des leucémies. D'une manière intrigante, de nombreux régulateurs de la transcription et des voies de signalisation contrôlant le développement des cellules sanguines sont évolutivement conservés des humains à Drosophila melanogaster, qui est donc utilisée comme organisme modèle pour étudier les mécanismes sous-jacents à la spécification des lignages sanguins et au contrôle de l'homéostasie des cellules sanguines. Les membres de la famille Myeloid Leukemia Factor (MLF) ont été impliqués dans l'hématopoïèse et dans la transformation oncogénique des cellules sanguines, mais leur fonction et leur mécanisme d'action moléculaire restent insaisissables. Des travaux précédents chez la Drosophile ont montré que MLF stabilise le facteur de transcription de type RUNX Lozenge (LZ) et contrôle le nombre de cellules sanguines LZ+. Au cours de ma thèse, j'ai cherché à déchiffrer le mécanisme moléculaire d'action de MLF sur Lozenge dans les cellules sanguines. Par une approche protéomique puis par des expériences de co-immunoprécipitation dans les cellules de Drosophile Kc167, nous avons identifié le co-chaperon de type Hsp40 DnaJ-1, et son partenaire le chaperon Hsc70-4, comme deux partenaires de MLF. De façon importante, nous avons montré que l'inhibition de l'expression de DnaJ-1 ou de Hsc70-4 dans les cellules Kc167 induit une réduction du niveau de protéine Lozenge et une diminution de sa capacité à activer la transcription très semblable à celles observées suite à l'inhibition de l'expression de MLF. De plus, la sur-expression de mutants de DnaJ-1 incapables d'activer le chaperon Hsc70-4 entraîne aussi une réduction du niveau de Lozenge et de sa capacité de transactivation et des expériences de coimmunoprécipitation montrent que Lozenge interagit avec MLF, DnaJ-1 et Hsc70-4. Nos résultats suggèrent donc que MLF agit au sein d'un complexe chaperon composé de DnaJ-1 et Hsc70-4 pour contrôler le niveau de Lozenge. En utilisant différents mutants de MLF ou DnaJ-1, nous avons montré que MLF et DnaJ-1 interagissent ensemble et avec Lozenge via des domaines phylogénétiquement conservés. D'autre part, des expériences de GST " pull down " in vitro suggèrent que ces trois protéines peuvent interagir ensemble directement. Nous proposons donc que MLF et DnaJ-1 contrôlent le niveau de protéine Lozenge en interagissant avec elle et en favorisant son repliement et/ou sa solubilité via l'activité chaperon de Hsc70-4. En parallèle, nous avons étudié la fonction de DnaJ-1 in vivo dans le développement des cellules sanguines de la Drosophile. Nos résultats montrent que, comme mlf, la perte de dnaj-1 s'accompagne d'une augmentation de la taille et du nombre des cellules sanguines LZ+, ainsi que d'une hyperactivation de la voie de signalisation Notch dans ces cellules. Nos résultats suggèrent que des hauts niveaux de Lozenge sont nécessaires pour contrôler le nombre et la taille des cellules LZ+ et pour inhiber l'expression de Notch. Nous proposons que le complexe MLF/DnaJ-1 contrôle le développement du lignage LZ+ en régulant le niveau de protéine Lozenge, et ainsi le niveau d'activité de la voie Notch. En conclusion, nos résultats ont mis à jour un lien fonctionnel entre MLF, le co-chaperon de type Hsp40 DnaJ-1 et un facteur de transcription de type RUNX, qui pourrait être conservé dans d'autres espècesHematopoiesis is the process of formation of fully differentiated blood cells from hematopoietic stem cells (HSCs). This process is tightly controlled by the integration of developmental and homeostatic signals to ensure the generation of an appropriate number of each blood cell type. At the molecular level, the regulation of this developmental process is mediated by a number of transcription factors, especially by members of the RUNX family, and mutations affecting these factors are at the origin of numerous hemopathies, including leukemia. Intriguingly, many transcriptional regulators and signaling pathways controlling blood cell development are evolutionarily conserved from humans to Drosophila melanogaster. Hence, the fruit fly has become a potent and simplified model to study the mechanisms underlying the specification of blood cell lineages and the regulation of blood cell homeostasis. Members of the Myeloid Leukemia Factor (MLF) family have been implicated in hematopoiesis and in oncogenic blood cell transformation, but their function and molecular mechanism of action remain elusive. Previous work in Drosophila showed that MLF stabilizes the RUNX transcription factor Lozenge (LZ) and controls the number of LZ+ blood cells. During my PhD, I sought to further decipher the molecular mechanism of action of MLF on Lozenge during blood cell development. Using a proteomic approach in Drosophila Kc167 cells, we identified the Hsp40 co-chaperone family member DnaJ-1 and its chaperone partner Hsc70-4 as two partners of MLF. These interactions were confirmed by co-immunoprecipitations and in vitro pull-down assays. Importantly, we found that knocking down DnaJ-1 or Hsc70-4 expression in Kc167 cells caused a reduction in the level of Lozenge protein and a concomitant decrease in Lozenge transactivation activity, which were very similar to those caused by MLF knock-down. Similarly, over-expression of two DnaJ-1 mutants that are unable to stimulate the chaperone activity of Hsc70-4 also decreased Lozenge level and impaired its capacity to activate transcription. These results suggest that MLF could act within a chaperone complex composed of DnaJ-1 and Hsc70-4 to control Lozenge stability and activity. Along that line, we showed by co-immunoprecipitation that Lozenge interacts with MLF, DnaJ-1 and Hsc70-4, respectively. Using various truncated mutants of MLF or DnaJ-1, we showed that MLF and DnaJ-1 interact and together with Lozenge through their conserved MLF homology domain (MHD) and C-terminal region, respectively. Furthermore, in vitro GST pull-down assays suggested that the interactions between MLF, DnaJ-1 and Lozenge are direct. Thus, we propose that MLF and DnaJ-1 control Lozenge protein level by interacting with it and by promoting its folding and/or solubility via the Hsc70 chaperone machinery. In parallel, we assessed DnaJ-1 function in Drosophila blood cells in vivo using a null allele of dnaj-1 generated by CRISPR/Cas9 technique. We found that, like mlf, dnaj-1 mutation leads to an increase in the number and size of LZ+ blood cells, as well as to an over-activation of the Notch signaling pathway in these cells. Moreover, our data suggested that high levels of active Lozenge are required to control the number and size of LZ+ blood cells, and to down-regulate Notch expression. We propose that the MLF/DnaJ-1 complex controls LZ+ blood cell development in vivo by regulating Lozenge protein level/activity and thereby Notch pathway activation. In sum, our results establish a functional link between MLF, the Hsp40 co-chaperone DnaJ-1 and the RUNX transcription factor Lozenge, which could be conserved in other species
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Sha, Xiaojin. "Translation initiation factor 4E binding protein 1,2 (4E-BP1,2) in hematopoiesis and stress erythropoiesis". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2008. http://dx.doi.org/10.18452/15797.
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Das Eukaryotische-Initiations faktor-4E Bindungsprotein (4E-BP) ist ein Inhibitor der Translationsinitiation. Nicht-phosphoryliertes 4E-BP bindet an den eukaryotischen Initiationsfaktor 4E (eIF4E). Diese Bindung blockiert die Rekrutierung des Initiationskomplexes eIF4F an die Cap-Struktur des 5´Endes von eukaryotischen zellulären mRNAs, was die Initiation der Translation verhindert. Phosphorylierung von 4E-BP durch die mTOR Kinase führt zur Dissoziation des 4E-BP/eIF4E Komplexes und erhöht die Verfügbarkeit von eIF4E, dies wird mit Zellproliferation assoziiert. Die Aktivität von eIF4E wird nicht nur von 4E-BP, sondern auch durch Phosporylierung reguliert, welche wiederum durch die "MAP-Kinase-Interacting-Protein-Kinase" (MNK) reguliert wird. Drei Isoformen von 4E-BP sind bekannt: 4E-BP1, 4E-BP2 and 4E-BP3. 4E-BP1 und 4E-BP2 sind an oxidativem und adipogenetischen Stress beteiligt. Beide Proteine werden im h?matopoetischen System gleich exprimiert, wohingegen 4E-BP3 nicht detektiert wird. 4E-BP1 wird während der Erythroblasten-Proliferation phosphoryliert. Aus diesem Grund habe ich die Hämatopoese und die durch Phenylhydrazine (PHZ) induzierte Stress-Erythropoese in 4E-BP1 und 4E-BP2 Knock-Out Mäusen und 4E-BP1,2 Doppel-Knock-Out Mäusen analysiert. Ich konnte zeigen, dass die Hämatopoese in 4E-BPs defizienten Mäusen nicht beeinflusst wird. Allerdings zeigten 4E-BP1,2-/- und 4E-BP2-/- Mäuse eine verspätete Antwort auf Phenylhydrazin (PHZ) induzierten erythropoetischen Stress. Gleichzeitig war die mRNA Translation von GATA-1, ein essentieller erythropoetischer Transkriptionsfaktor in Erythroblasten runterreguliert. Die Signaltransduktionswege mTOR und MNK1 waren bei erythropoetischen Stress aktiviert. Diese Daten zeigen, dass 4E-BP2, aber nicht 4E-BP1, notwendig ist um auf erythropoetischen Stress zu reagieren und deuten an, dass die 4E-BP gesteuerte translations-regulierende Maschinerie eine Rolle in der Stress-Erythropoese spielt.Translational regulation allows an organism to generate fast responses to environmental changes quickly. Eukaryotic initiation factor 4E binding protein (4E-BP) is an inhibitor of translation initiation. Unphosphorylated 4E-BP binds to eukaryotic initiation factor 4E (eIF4E) blocking recruitment of the initiation complex eIF4F to the cap structure at the 5´ terminus of eukaryotic cellular mRNAs. Thus initiation of translation is blocked. Phosphorylation of 4E-BP by the mTOR kinase causes disassociation of the 4E-BP/eIF4E complex and increases the availability of eIF4E. EIF4E activity is not only regulated by 4E-BP, but also phosphorylation which is regulated by MAP kinase - interacting protein kinase (MNK). Three isoforms of 4E-BP are known, termed 4E-BP1, 4E-BP2 and 4E-BP3. 4E-BP1 and 4E-BP2 are involved in oxidative and adipogenetic stresses in vivo. They are equally expressed in hematopoietic system, whereas 4E-BP3 is not detected. 4E-BP1 is phosphorylated during erythroblast proliferation. Erythroid differentiation is blocked by overexpresssion of eIF4E in tissue culture. These studies implied that 4E-BPs might play role in response to erythropoietic stress. I examined hematopoiesis and phenylhydrazine (PHZ) induced stress erythropoiesis in 4E-BP1 and 4E-BP2 individual knock out mice and 4E-BP1,2 compound knock out mice. I found that the hematopoiesis of 4E-BPs deficient mice were unaffected. However, 4E-BP1,2-/- and 4E-BP2-/- mice showed delayed response to phenylhydrazine (PHZ) induced erythropoietic stress. Simultaneously, the mRNA translation of GATA-1, which is the essential erythroid transcription factor, was downregulated in their erythroblasts. The signaling pathways through the mTOR and MNK1 were activated in erythropoietic stress. These data showed that 4E-BP2 but not 4E-BP1 was required for the response to erythropoietic stress and suggested that 4E-BP related translation regulatory machinery played a role in stress erythropoiesis.
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Hultquist, Anne. "Regulation and function of the Mad/Max/Myc network during neuronal and hematopoietic differentiation". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5070-9/.
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Hu, Nan. "Erk1/2 Signaling Pathway and Transcriptional Repressor Gfi1 in the Regulation of Neutrophil versus Monocyte Development in Response to G-CSF and M-CSF". University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1440089200.
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Renström, Jonas Verfasser], Jochen [Akademischer Betreuer] Graw, Robert A. J. [Akademischer Betreuer] Oostendorp e Angelika [Akademischer Betreuer] [Schnieke. "The regulation of hematopoiesis by stromal cells / Lars Jonas Mikael Renström. Gutachter: Jochen Graw ; Robert A. J. Oostendorp ; Angelika Schnieke. Betreuer: Robert A. J. Oostendorp". München : Universitätsbibliothek der TU München, 2010. http://d-nb.info/1013436938/34.
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Lung, Tina Kathy. "Analysis of Mouse EKLF/KLF2 E9.5 Double Knockout: Yolk Sac Morphology and Embryonic Erythroid Maturation". VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1821.
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Apostolov, Apostol. "Studying the posttranslational modifications of transcription factor Ikaros and their role in its function". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00923158.
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The main topic of my PhD studies was to investigate the role of sumoylation in the function of Ikaros transcription factor, that regulates the lymphocyte differentiation and function. Sumoylation is a posttranslational modification that can change the properties and regulate the function of a given protein. Up to now, one study addressed the question of how sumoylationmodulates Ikaros function. It shows that Ikaros is sumoylated in total primary thymocytes, and that this dynamic event modulates Ikaros' repressive function. It also describes two consensus sumoylation sites on Ikaros (K58 and K240), the sumoylation of which leads to loss of Ikaros repressive function in ectopic reporter gene assays. The final conclusion of the study is that sumoylation does not alter the nuclear localization of Ikaros but acts as a mechanism disrupting its participation in both histone deacetylase (HDAC) dependent and independent repression. My work shows the presence of additional sumoylation site on Ikaros and demonstrates that sumoylation does not significantly alter its interaction with the nucleosome remodelling and histone deacetylase (NURD) complex in T-cell lines. The functional analysis of sumo-deficientmutants indicates a complex role of this modification in regulating Ikaros' transcriptional properties. The identification of this new sumoylation site contributes to a better understanding of Ikaros' dual repressive - activating function and suggests the existence of conditional Ikaros' interacting partners. Moreover, the different Ikaros splicing isoforms would have differentsumoylation profiles, which would complete the knowledge of their functional diversity.
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Torres, Núñez Eva. "Sparc (Osteonectin): new insight into the function and regulation = Sparc (Osteonectin): nuevos conocimientos sobre sus funciones y regulación". Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/133023.
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The Extracellular Matrix (ECM) is a complex network secreted by cells that serves as a structural element in tissues and also influences their development and physiology. More specifically, the extracellular matrix helps cells to bind together and regulates several cellular functions such as adhesion, migration, proliferation and differentiation. It is composed of growth factors, proteoglycans, structural proteins and matricellular proteins.
Osteonectin, also named Sparc (Secreted Protein Acidic and Rich in Cysteine) or BM-40 (Membrane Protein-40), is a multifunctional glycoprotein that belongs to the matricellular protein family. This group modulates matrix-cellular interactions and takes part in several cell functions, rather than playing a role in the cell structure. Sparc is known to have high affinity with calcium ions and was first discovered as the major component of ECM in mineral tissues, although it has since been located in many other tissues. Sparc expression is high during early development but remains low in adult life. However, it is expressed in tissues under renewal, tissue repair or tumorigenesis. Since Sparc is able to interact with multiple molecules, many important functions have been attributed to this protein, including counteradhesion, the regulation of cell proliferation and angiogenic activity.
Analysis of the results obtained during this PhD Thesis leads to the following conclusions:
• Sparc is as an important regulator of embryonic haematopoiesis during early development in zebrafish. Specifically, it mediates erythroid progenitor cell development regulating gata1 and βe3globin expression.
• Similar defects in blood phenotypes of sparc and fgfs knockdowns and the capacity to partially rescue the fgf21 blood phenotype places sparc downstream of fgf21 signaling genetic network.
• UV exposure induces an increase in the p53 and sparc expression
• According with the conclusion 3, a possible molecular mechanism induced by sparc after UV-radiation is suggested to be the responsible in part of the increment in developmental abnormalities.
• 5’UTR-intron is key transcriptional regulatory region of sparc gene since gene-construct containing simply this region predominantly displayed GFP expression in notochord, intermediate cell mass, otic vesicle, olfactory epithelium and muscle fibers in injected zebrafish embryos.
• sparc is transcriptionally regulated by DNA methylation through the CpG island detected immediately upstream the 5’ translation start site which is located within the intron sequence.
• Turbot Sparc protein keeps the same protein structure exhibited by all vertebrate Sparc proteins. The predicted turbot Sparc protein sequence shares high similarity to the Sparc proteins of other vertebrates. Phylogenetic analysis also indicated that turbot Sparc clusters together with its vertebrate orthologs. Additionally, we found that the expression pattern of Turbot sparc is comparable to other teleost species. Therefore, these results suggest a strong evolutionary pressure to conserve this protein and indicate that there should be an evident conservation of function.
• sparc mRNA expression showed a dynamic stage-specific expression during post-embryonic turbot development with high levels at metamorphic climax, indicating that it might be necessary for turbot metamorphosis.Osteonectina, también llamada Sparc o BM-40, es una glicoproteína multifuncional que pertenece a la familia de las proteínas matricelulares de la matriz extracelular. Este grupo modula las interacciones entre la matriz y las células e interviene en múltiples funciones más que jugar un papel en la estructura celular. Se sabe que Sparc tiene una alta afinidad por los iones calcio y fue descubierta por primera vez como el componente mayoritario de la matriz extracelular de tejidos mineralizados. Más tarde, se localizó Sparc en muchos otros tejidos. La expresión de Sparc es alta durante el desarrollo temprano y disminuye durante la edad adulta. Sin embargo, su expresión aumenta en tejidos que requieren cierto grado de renovación, reparación o en tumorigénesis. Debido a que Sparc es capaz de interactuar con múltiples moléculas, se le han atribuido importantes funciones como antiadhesión, regulación del ciclo celular y actividad angiogénica. Debido al poco conocimiento respecto a la regulación de Sparc y los papeles contradictorios en diferentes tejidos, el objetivo principal de esta tesis es contribuir a un mayor entendimiento de este gen en peces teleósteos. En esta tesis demostramos: 1. Sparc es un regulador importante en hematopoyesis embriogénica durante el desarrollo temprano del pez cebra. 2. Localizamos sparc corriente abajo de fgf21 en esta cascada de regulación. 3. La radiación ultravioleta es capaz de inducir un incremento en la expresión de p53 y Sparc. 4. Dado que sparc está altamente expresada en embriones expuestos a radiación ultravioleta, este gen puede estar implicado en el incremento de malformaciones durante el desarrollo. Así, se sugiere que posiblemente sparc sea capa de inducir un mecanismo molecular en respuesta a la exposición de UV. 5. El intrón localizado entre las dos regiones 5’UTR es clave para regulación transcripcional de sparc ya que el vector conteniendo únicamente esta secuencia asociada a GFP es capaz de expresar fluorescencia en notocorda, ICM, vesícula ótica, bulbo olfatorio y fibras musculares, lugares donde se sabe que sparc está presente tanto en pez cebra como en otras especies de teleósteos. 6. Sparc está regulada a nivel de la transcripción por metilación del ADN. Concretamente, la isla CpG detectada en el intrón es susceptible a procesos de metilación. 7. Tanto la secuencia aminoacídica de Sparc como los lugares de expresión en larvas de rodaballo (Scophthalmus maximus) están altamente conservados cuando se comparan con las secuencias existentes en otras especies. 8. Sparc tiene un papel durante la metamorfosis de rodaballo por su alta expresión en etapas premetamórficas.
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Perrod, Chiara. "Epigenetic PU.1 silencing in myeloid leukemia by mimicrying a T cell specific chromatin loop". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16863.
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Veränderungen in der lokalen Chromatinstruktur beeinflussen die dynamische Regulation von Genen, welche für die Differenzierung notwendig sind. PU.1 ist ein Master-Transkriptionsfaktor in der Hämatopoese und wird streng reguliert, um ein zelllinienspezifisches Expressionsmuster zu erzielen. Hohe Konzentrationen von PU.1 sind für myeloische Differenzierung erforderlich. In B-Zellen wird PU.1 mittelstark exprimiert und muss aktiv runterreguliert werden, um eine Ausdifferenzierung der multipotenten Vorläuferzellen zu T-Zellen zu ermöglichen. Derzeit ist wenig über die Regulierung von PU.1 in T-Zellen bekannt. Darüber hinaus wurde eine abnormale Expression von PU.1 in verschiedenen Leukämieerkrankungen beobachtet. Mittels eines genome-wide Chromatin-Interaktions-Screens konnten wir einen cis-Repressor mit insulierender Kapazität identifizieren, welcher mittels eines Chromatinloops die Promotoraktivität von PU.1 in T-Zellen, jedoch nicht in myeloischen oder B-Zellen blockiert. Sowie Looping als auch Insulation erfordern die Bindung des Chromatin-Regulatorprotein CTCF. Im Gegensatz zu normalen myeloischen Zellen finden wir, dass Krebszellen aus myeloischen Leukämie Patienten diese T-Zell-spezifische repressive Chromatinstruktur aufweisen, was einen räumlichen Kontakt des Insulator mit dem PU.1 Promotor ermöglicht. Die Ergebnisse dieser Arbeit beschrieben das CTCF gesteuerte „long distance looping“ als ein neuer molekularer epigenetischer Mechanismus, um Transkriptionsfaktor PU.1 in T-Zellen runterzuregulieren, und zeigen zum ersten mal, dass Krebszellen die Chromatinstruktur anderer Zelllinien imitieren können, um die Expression von Differenzierungsgenen zu blockieren.Alterations in the local chromatin structure orchestrate the dynamic regulation of differentiation promoting genes. PU.1 is a master transcription factor in hematopoiesis. PU.1 gene must be tightly regulated to achieve lineage specific expression pattern. High levels of PU.1 are required for myeloid commitment: it is expressed at intermediate level in B-cells and must be actively silenced to permit T cell development from early multipotent progenitors. However, little is known of how PU.1 is regulated in T-cells. Moreover, aberrant PU.1 expressions have been observed in multiple leukemias. Using a genome-wide chromatin interaction screen we identified a cis-repressor with insulating capacity that undergoes long-distant chromatin looping to block PU.1 promoter activity in T cells but not myeloid or B cells. Looping and repression requires binding of the chromatin regulator protein CTCF. In contrast to normal myeloid cells, we found that cancer cells from myeloid leukemia patients adopt the T cell specific repressive chromatin structure bringing the insulator into spatial contact with the PU.1 promoter. These results identify CTCF controlled long-distant insulator looping as a novel mechanism to silence lineage-opposing transcription factor expression, and reveal that cancer cells can mimic the chromatin confirmation of another lineage to block expression of differentiation driving genes.
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Corbel, Stéphane. "Mise en évidence d'un transport bi-directionnel d'histamine dans les progéniteurs hématopoïétiques murins". Paris 5, 1997. http://www.theses.fr/1997PA055001.
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L'histamine, un médiateur forme après décarboxylation de l'histidine par une enzyme l'histidine décarboxylase (HDC), est produite par différents types cellulaires du système immunitaire ou nerveux. Sa qualité d'agent immunomodulateur et de neurotransmetteur est clairement démontrée. Son rôle dans les phénomènes de prolifération et différenciation cellulaires est également suggéré par de nombreux faits expérimentaux. L'histamine pourrait aussi être impliquée dans l'hématopoïèse, et quelques arguments sont en faveur de cette possibilité. Ainsi, dans le laboratoire, nous avons montré une production importante d'histamine par les cellules hématopoïétiques en réponse à divers stimuli. Cette histamine endogène est indispensable à la mise en cycle des cellules immatures de la moelle osseuse stimulées par l'il-3. Au cours de cette thèse, nous avons mis en évidence un système bidirectionnel d'entrée et de sortie d'histamine dans les progeniteurs hématopoïétiques. Ce transport est inhibe spécifiquement par les antagonistes des récepteurs h#3 de l'histamine, dont un représentant, le iodoproxyfan, disponible sous sa forme radio marquée, est un ligand typique et efficace. Toutefois, nous avons montré que le mécanisme de captage d'histamine n'implique pas une fixation sur ces récepteurs h#3, et est dépendant des échanges ioniques. Le blocage de la libération d'histamine produite en réponse à l'il-3 par les inhibiteurs du transport bidirectionnel, s'accompagne d'une augmentation du contenu intracellulaire. Cet accroissement du taux d'histamine intracellulaire ne résulte pas d'une accumulation totale de l'histamine non libérée. La production globale d'histamine est en fait atténuée en présence de ces antagonistes et cette diminution s'observe tant au niveau de la protéine HDC, dont l'activité est altérée, qu'au niveau de l'expression du gène, codant cette enzyme, qui est réduite. Nos résultats suggèrent que ces modifications seraient consécutives à l'augmentation de la concentration intracellulaire d'histamine. L'existence d'un rétrocontrôle de la synthèse d'histamine permet d'envisager une nouvelle approche quant aux processus qui régissent la production de cette amine dans différents tissus. De plus, outre l'histamine, les mêmes progeniteurs hématopoïétiques produisent également de l'il-4 et de l'il-6. Des résultats préliminaires montrent qu'une forte concentration intracellulaire en histamine modifie la synthèse de ces cytokines. Ils suggèrent que l'histamine pourrait prendre une part importante dans le contrôle de l'hématopoïèse et de l'immunité dont ces cytokines sont des intermédiaires influents.
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Oakley, Erin J. "GENETIC REGULATION OF HEMATOPOIETIC STEM CELL AGING". UKnowledge, 2008. http://uknowledge.uky.edu/gradschool_diss/659.
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It is well documented that both quantitative and qualitative changes in the murine hematopoietic stem cell (HSC) population occur with age. In mice, the effect of aging on stem cells is highly strain-specific, thus suggesting genetic regulation plays a role in HSC aging. In C57BL/6 (B6) mice, the HSC population steadily increases with age, whereas in DBA/2 (D2) mice, this population declines. Our lab has previously mapped a quantitative trait locus (QTL) to murine chromosome 2 that is associated with the variation in frequency of HSCs between aged B6 and D2 mice. In these dissertation studies, I first aim to characterize the congenic mouse model which was generated by introgressing D2 alleles in the QTL onto a B6 background. Using a surrogate assay to mimic aging, I analyzed the cell cycle, apoptotic and self-renewal capabilities of congenic and B6 HSCs and show that D2 alleles in the QTL affect the apoptotic and selfrenewal capabilities of HSCs. In the second aim of these studies, I used oligonucleotide arrays to compare the differential expression of B6 and congenic cells using a population enriched for primitive stem and progenitor cells. Extensive analysis of the expression arrays pointed to two strong candidates, the genes encoding Retinoblastoma like protein 1 (p107) and Sorting nexin 5 (Snx5). B6 alleles were associated with increased p107 and Snx5 expression in old HSCs therefore both genes were hypothesized to be positive regulators of stem cell number in aged mice. Finally, in the third aim of these studies, I show that the individual overexpression of p107 and Snx5 in congeic HSCs increases day35 cobblestone area forming cell (CAFC) numbers, therefore confirming their roles as positive regulators of HSC number in vitro. These studies uncover novel roles for p107 and Snx5 in the regulation of HSC numbers and provide additional clues in the complex regulation of HSC aging.
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Nottingham, Wade. "Transcriptional regulation of Runx1 in the developing haematopoietic system". Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670091.
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Hastreiter, Araceli Aparecida. "Avaliação de aspectos regulatórios da hematopoese em desnutrição proteico-energética experimental: papel das células endoteliais derivadas das células tronco mesenquimais medulares". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-22102014-155543/.
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A desnutrição proteico-energética (DPE) provoca anemia e leucopenia decorrente da redução de precursores hematopoéticos e comprometimento da produção de mediadores indutores da hematopoese, bem como alterações estruturais e ultra-estruturais na matriz extracelular medular. A hematopoese ocorre em nichos medulares distintos - endosteal e perivascular - que modulam os processos de diferenciação, proliferação e auto-renovação da célula tronco hematopoética (CTH). As células tronco mesenquimais (CTM) tem um papel importante na formação destes nichos, através da sua diferenciação nos diversos tipos celulares que os compõe. Adicionalmente, a CTM pode modular a função de outras células, como a CTH e a célula endotelial (CE) medular, através da liberação de diversos fatores de crescimento e citocinas. As CE expressam proteínas que regulam a diferenciação e movimentação das CTH na MO. Há sinais que a CTM pode ser a precursora da CE medulares, pois in vitro a CTM pode se diferenciar em CE-like. Desta forma, a CTM é um ponto chave no estudo das alterações causadas pela DPE no nicho perivascular e sobre a regulação da hematopoese. Neste trabalho, investigamos se a DPE afeta a diferenciação in vitro da CTM medular em CE-like e avaliamos se essas células apresentam diferentes capacidades em produzir alguns mediadores regulatórios da hematopoese (CXCL-12, SCF, Ang-1, IL-11, GM-CSF e TFG-β), bem como possíveis alterações no perfil de expressão gênica de marcadores de função das CTM e CE-like. Utilizamos camundongos C57BL/6 machos, divididos em grupos Controle e Desnutrido, sendo que o grupo Controle recebeu ração normoprotéica (12% caseína) e o grupo Desnutrido recebeu ração hipoprotéica (2% caseína), ambos durante 5 semanas. Após este período, os animais foram eutanasiados, foi realizada a avaliação nutricional e hematológica, caracterizando a DPE. As CTM foram isoladas, caracterizadas e diferenciadas in vitro em CE-like, o que foi evidenciado pela maior expressão gênica de NT5E, FLT1, KDR, PECAM1 e VCAM1. Avaliamos a expressão dos genes CDH5, CSPG4, LEPR, NES, CSF1, CSF2, CSF3, MCAM, PROM1, ANGPT1, CXCL12, ENG, IGF1, IL3, IL11, KITL, TGFB1, WNT3A, WNT5A, ICAM1, PDGFB1 e VWF. Encontramos alterações causadas pela DPE na expressão gênica e quantificação de CXCL-12, SCF e Ang-1, os quais mostraram que as células avaliadas do grupo Desnutrido encontram-se em um estado \"pró-proliferativo\", em um esforço para restabelecer a hematopoese na DPE. Entretanto, foi observado neste trabalho e nos demais trabalhos do grupo que há hipoplasia medular na DPE e, portanto, pode-se inferir que as alterações hematopoéticas observadas na DPE não são ocasionadas por alterações na síntese de SCF, CXCL-12 ou Ang-1.Protein-energy malnutrition (PEM) causes anemia and leukopenia as it reduces hematopoietic precursors, impairs the production of mediators that induce hematopoiesis and alters structural and ultrastructural changes in bone marrow (BM) extracellular matrix. Hematopoiesis occurs in distinct BM niches - endosteal and perivascular - which modulate the processes of differentiation, proliferation and self-renewal of hematopoietic stem cell (HSC). Mesenchymal stem cells (MSC) play an important role in the formation of these niches through their differentiation in several cell types that compose them. Additionally, MSC can modulate the function of other cells, such as HSC and endothelial cells (EC), through the release of several growth factors and cytokines. The EC express proteins that regulate the differentiation and migration of HSC in the BM. MSC seem to be the precursor of medullary EC because in vitro MSC can differentiate into EC-like cells. Thus, MSC are a key point in the study of changes caused by DPE on the perivascular niche and on the regulation of hematopoiesis. In this study, we investigated whether PEM would affect BM-MSC in vitro differentiation into EC-like cells and evaluated whether these cells would have distinct capacities of producing some regulatory mediators of hematopoiesis (CXCL- 12, SCF, Ang-1, IL-11, GM -CSF and TFG-β), as well as analyzed possible changes in the gene expression profile of MSC function and EC-like cells related markers. C57BL/6 mice were divided into Control and Malnourished groups, which received for 5 weeks, respectively, a normal protein diet (12% casein) and a low protein diet (2% casein). After this period, animals were euthanized, nutritional and hematological evaluations were performed, featuring the PEM. MSC were isolated, characterized and differentiated in vitro into EC-like cells, which were evidenced by increased gene expression of NT5E, FLT1, KDR, PECAM1 and VCAM1. The expression of CDH5, CSPG4, LEPR, NES, CSF1, CSF2, CSF3, MCAM, PROM1, ANGPT1, CXCL12, ENG, IGF1, IL3, IL11, KITL, TGFB1, Wnt3a, WNT5A, ICAM1, PDGFB1 and VWF genes was also evaluated. Changes caused by PEM on gene expression and quantification of CXCL-12, SCF and Ang-1 were found, indicating that tested cells from the Malnourished group were in a \"pro-proliferative\" state in an effort to restore hematopoiesis. However, our results are in accordance to the literature regarding bone marrow hypoplasia as a consequence of PEM. Therefore, we infer hematopoietic changes observed in this work are not related to changes in the synthesis of SCF, 12 CXCL-12 or Ang-1.
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McKim, Daniel Boyce. "Neuroimmune and Hematopoietic Regulation of Stress-Induced Anxiety". The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492079844476452.
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Tshuikina, Wiklander Marina. "Epigenetic Regulation of Gene Transcription in Hematopoietic Tumors". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9206.
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Kriz, Vitezslav. "The Role of the SHB Adapter Protein in Cell Differentiation and Development". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6850.
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Ghadie, Mohamed A. "Analysis and Reconstruction of the Hematopoietic Stem Cell Differentiation Tree: A Linear Programming Approach for Gene Selection". Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32048.
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Stem cells differentiate through an organized hierarchy of intermediate cell types to terminally differentiated cell types. This process is largely guided by master transcriptional regulators, but it also depends on the expression of many other types of genes. The discrete cell types in the differentiation hierarchy are often identified based on the expression or non-expression of certain marker genes. Historically, these have often been various cell-surface proteins, which are fairly easy to assay biochemically but are not necessarily causative of the cell type, in the sense of being master transcriptional regulators. This raises important questions about how gene expression across the whole genome controls or reflects cell state, and in particular, differentiation hierarchies. Traditional approaches to understanding gene expression patterns across multiple conditions, such as principal components analysis or K-means clustering, can group cell types based on gene expression, but they do so without knowledge of the differentiation hierarchy. Hierarchical clustering and maximization of parsimony can organize the cell types into a tree, but in general this tree is different from the differentiation hierarchy. Using hematopoietic differentiation as an example, we demonstrate how many genes other than marker genes are able to discriminate between different branches of the differentiation tree by proposing two models for detecting genes that are up-regulated or down-regulated in distinct lineages. We then propose a novel approach to solving the following problem: Given the differentiation hierarchy and gene expression data at each node, construct a weighted Euclidean distance metric such that the minimum spanning tree with respect to that metric is precisely the given differentiation hierarchy. We provide a set of linear constraints that are provably sufficient for the desired construction and a linear programming framework to identify sparse sets of weights, effectively identifying genes that are most relevant for discriminating different parts of the tree. We apply our method to microarray gene expression data describing 38 cell types in the hematopoiesis hierarchy, constructing a sparse weighted Euclidean metric that uses just 175 genes. These 175 genes are different than the marker genes that were used to identify the 38 cell types, hence offering a novel alternative way of discriminating different branches of the tree. A DAVID functional annotation analysis shows that the 175 genes reflect major processes and pathways active in different parts of the tree. However, we find that there are many alternative sets of weights that satisfy the linear constraints. Thus, in the style of random-forest training, we also construct metrics based on random subsets of the genes and compare them to the metric of 175 genes. Our results show that the 175 genes frequently appear in the random metrics, implicating their significance from an empirical point of view as well. Finally, we show how our linear programming method is able to identify columns that were selected to build minimum spanning trees on the nodes of random variable-size matrices.
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Xu, Dawei. "Telomerase activity and its regulation in malignant hematopoietic cells /". Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3815-6/.
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LIANG, YING. "GENETIC REGULATION OF HEMATOPOIETIC STEM CELL NUMBERS IN MICE". UKnowledge, 2005. http://uknowledge.uky.edu/gradschool_diss/418.
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Hematopoietic stem cells (HSCs) transplantations are widely used for the treatment of hematological and non-hematological disorders in clinic. Successful transplantation requires sufficient number and efficient homing of HSCs. Many studies have focused on developing an effective strategy to expand functional HSC population. Some regulatory molecules have been recently shown great promise for controlling the amplification of HSCs. In these dissertation studies, I first aim to identify gene(s) and their allelic variants contributing to strain-specific difference in HSC numbers between C57BL/6 (B6, low) and DBA/2 (D2, high) mice by using a classic forward genetic approach. Firstly, 3 quantitative trait loci (QTL) on chromosome (Chr) 3,5 and 18 were mapped by linkage analyses and confirmed in congenic mice. Secondly, Chr.3 QTL affected several HSC number-related biological processes. The D2 allele increased cycling and self-renewal whereas it decreased apoptotic rates of HSCs. Both actions conspired to increase HSC population size. Lastly, a small number of differentially-expressed genes was identified in Chr.3 congenic HSCs by a microarray-based candidate gene method, and the differential expression of one candidate, latexin, was found to relate to HSC number variations. Our studies report the strong evidence for the potential functions of latexin in HSC number regulation, and they are important for understanding molecular mechanisms of stem cell regulation and developing effective stem cell expansion strategies for clinical applications. In the second part of my studies, I studied homing and engraftment capabilities of HSCs. By using functional assays for progenitor and stem cells, I first reported the absolute homing efficiencies of murine young or old donor cells into young or old recipient mice. The results indicated that homing of primitive hematopoietic cells was not efficient and significantly decreased by aging of donors and recipients. The proliferation and differentiation states of HSCs were also impaired by homing itself, as well as by donors' and recipients age. Moreover, the hematopoietic reconstitution dynamics following transplantation were also affected by aging. Together, these findings will provide useful information for clinical applications especially when older individuals increasing serve as stem cell donors for elderly patients.
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Copley, Michael Rebin. "Regulation of developmental changes in hematopoietic stem cell self-renewal". Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44819.
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Mouse hematopoietic stem cells (HSCs) undergo a post-natal transition in several properties, including a marked reduction in their self-renewal activity. To investigate the molecular basis of this difference, we devised a single strategy to isolate fetal and adult HSCs at similarly high frequencies. This strategy, involving fluorescence-activated cell sorting of cells with a CD45⁺EPCR⁺CD48-CD150⁺ (ESLAM) phenotype, allows isolation of HSCs at a frequency of ~1 in 2 from all developmental time points tested (mouse embryonic day (E) 14.5 to adult). Comparison of differentially expressed genes in primitive populations of fetal and adult hematopoietic cells showed that heightened expression of Hmga2 was a feature of fetal as compared to adult HSCs. We also identified let-7 microRNAs (miRNAs) and a negative regulator of their biogenesis, Lin28b, to be expressed in an opposite and similar pattern to Hmga2, respectively. Since Hmga2 is a well-established target of let-7 miRNAs, we hypothesized that the Lin28b-let-7-Hmga2 axis plays a central role in the determination of fetal versus adult HSC self-renewal identity. We also found that Lin28 overexpression in adult HSCs restores a higher, fetal-like, self-renewal potential in them, and this effect is phenocopied by direct overexpression of Hmga2. Conversely, HSCs from fetal Hmga2-/- mice display a prematurely acquired adult-like self-renewal activity. Importantly, we show that Lin28-mediated activation of Hmga2 expression, which is responsible for the activation of a fetal-like self-renewal potential in adult HSCs, is not the mechanism by which Lin28 reprograms adult HSCs to undergo fetal-like B-cell differentiation. Together, these findings suggest a model of development in which Lin28b acts as a master regulator and Hmga2 serves as a more specific downstream modulator of HSC self-renewal. These findings may help inform strategies to improve the therapeutic use of HSCs. Furthermore, since Lin28b and Hmga2 are oncogenes, we speculate that the fetal/neonatal specific pattern of expression of these genes may contribute to the pathogenesis of pediatric leukemias.
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Van, der Wath Richard Carl. "Computational modelling of hematopoietic stem cell division and regulation dynamics". Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608642.
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Sharma, Devyani. "Regulation Of Hematopoietic Stem Cells By Lipid and Mitochondrial Metabolism". University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563295190003946.
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Foltz, Ian Nevin. "Regulation of the stress-activated protein kinase pathways in hematopoietic cells". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ38887.pdf.
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Lee-Sayer, Sally. "Hyaluronan binding and CD44 in regulating hematopoiesis and CD8 T cell response". Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61999.
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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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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.