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Javier, Jose Emmanuel F. "Increased TGF-beta Signaling Drives Different Hematopoietic Disease Outcomes following Stress Hematopoiesis." University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1617109578665394.
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Lin, Xionghui. "Hematopoiesis in a Crustacean." Doctoral thesis, Uppsala universitet, Jämförande fysiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-121000.
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Hemocytes (blood cells) play an important role in the immune response in invertebrates, and thus the regulation of hemocyte homeostasis (hematopoiesis) is essential for the host survival against pathogens. Astakine 1, a homologue to vertebrate prokineticins, was first identified in the freshwater crayfish Pacifastacus leniusculus as a cytokine, and was found to be necessary for new hemocyte synthesis and release in vivo, and also to induce spreading and proliferation of Hematopoietic tissue cells (Hpt cells, precursor of hemocytes) in vitro. The work of this thesis is aimed to further our understanding of the molecular mechanisms involved in astakine 1 induced hematopoiesis. Crayfish transglutaminase (Tgase) has been identified in the hemocytes, and is essential for the coagulation reaction. Interestingly this enzyme is exceedingly abundant in the Hpt cells, and the spreading of Hpt cells induced by astakine 1 was accompanied by sequential loss of TGase activity from the surface of these cells. This loss of TGase activity may be an important effect of astakine 1, resulting in recruiting new hemocytes into the circulatory system. Although astakine 1 contain a prokineticin domain, it lacks the conserved N-terminal AVIT motif present in its vertebrate homologues. This motif is important for vertebrate prokineticins to interact with their receptors, indicating a different receptor interaction for crayfish astakine 1. Astakine 1 was indeed found to interact with a completely different receptor, the β-subunit of ATP synthase, on a portion of Hpt cells, and subsequently block its extracellular ATP formation. Surface ATP synthase has been reported on numerous mammalian cells, but now for the first time in an invertebrate. The activity of ATP synthase on the Hpt cells may be important for the survival and proliferation of Hpt cells, but the underlying mechanisms remain further study. With the finding of a second type of astakine in crayfish, invertebrate astakines can be divided into two groups: astakine 1 and astakine 2. The properties of astakine 2 are different from those of astakine 1 both in structure and function. In primary cell culture of Hpt cells, only astakine 1 can promote proliferation as well as differentiation into semigranular cells, whereas astakine 2 may play a potential role in the maturation of granular cells. Moreover, a novel cysteine rich protein, Pacifastacus hematopoiesis factor (PHF), was found to be one target gene of astakine 1 in Hpt cells. Down regulation of PHF results in increased apoptosis in Hpt cells in vitro, and in vivo silencing PHF leads to a severe loss of hemocytes in the animal. Therefore astakine 1 acquires the anti-apoptosis ability by inducing its downstream gene PHF in the Hpt cells. With its ability to promote the survival, proliferation and differentiation of Hpt cells, astakine 1 is proven to be an important hematopoietic growth factor.
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Benson, Eric Ashley. "Loss of SIMPL increases TNFalpha sensitivity during hematopoiesis." Connect to resource online, 2008. http://hdl.handle.net/1805/1851.
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Thesis (Ph. D.)--Indiana University, 2008.<br>Title from screen (viewed June 24, 2009). Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Maureen Harrington. Includes vita. Non-Latin script record. Includes bibliographical references (leaves 126-132).
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Urbieta, Maitee. "Regulatory T Cells and Hematopoiesis in Bone Marrow Transplantation." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/463.
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CD4+CD25+FoxP3+ regulatory T cells (Treg) possess the capacity to modulate both adaptive and innate immunity. Due to their suppressive nature, Treg cells have been studied and tested in a variety of scenarios in an attempt to ameliorate undesired immune responses. While graft versus host disease (GVHD) has in fact emerged as the first clinical application for human Treg cells (Riley et al. 2009), equally important are issues concerning hematopoietic engraftment and immune reconstitution. Currently, little is known about the effect(s) that regulatory T cells may exert outside the immune system in this context. Based on cytokine effector molecules they can produce we hypothesized that Treg cells could regulate hematopoietic phenomena. The studies portrayed in this dissertation demonstrate that Treg cells can differentially affect the colony forming activity of myeloid and erythroid progenitor cells. In-vitro as well as in-vivo findings demonstrate the ability of Tregs to inhibit and augment the differentiation of primitive and intermediate myeloid (interleukin (IL)-3 driven) and late erythroid (erythropoietin driven) hematopoietic progenitor cells, respectively. The inhibitory and enhancing affects appeared to be mediated by independent pathways, the former requiring cell-cell contact, major histocompatibility complex (MHC) class II expression on marrow cells and involving transforming growth factor beta (TGF-beta), whereas the latter required interleukin (IL)-9 and was not contact dependent. Strikingly, we observed that in addition to regulating hematopoietic activity in normal primary BM cells, Tregs were also capable of suppressing colony forming activity by the myelogenous leukemia cell line NFS-60. Furthermore, studies involving endogenous Treg manipulations in-situ (i.e. depletion of these cells) resulted in elevated overall myeloid colony activity (CFU-IL3) and diminished colony numbers of erythroid precursors (CFU-E) in recipients following BMT. Consistent with these results, it was found that upon co-transplant with limiting numbers of bone marrow cells, exogenously added Treg cells exert in-vivo regulation of myeloid and erythroid CFU activity during the initial weeks post-transplantation. This regulation of hematopoietic activity by freshly generated Tregs upon transplantation led to the elaboration of a second hypothesis; following lethal total body irradiation (TBI) the host microenvironment facilitates regulatory T cell activation/effector function. Substantial evidence has accumulated in support of this hypothesis, for example we demonstrate up-regulation of surface molecules such as GARP and CD150/SLAM, which have been previously reported as indicators of Treg activation following TCR signaling and co-stimulation, occurs in donor (reporter) Treg populations. Acquisition of an activated phenotype and hence of effector/modulatory function is consistent with the previous in-vivo observations, indicating that both recipient and donor Treg cells can influence hematopoietic progenitor cell activity post-transplant. Finally, the present studies may be of great relevance in the emerging field of Treg cell based immunotherapy for prevention and/or treatment of HSCT complications.
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Syrjänen, R. (Riikka). "TIM family molecules in hematopoiesis." Doctoral thesis, Oulun yliopisto, 2014. http://urn.fi/urn:isbn:9789526204246.
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Abstract Hematopoietic cells, i.e., erythrocytes, platelets and white blood cells, differentiate from hematopoietic stem cells in a process that is similar in vertebrates. Hematopoiesis is regulated by molecules expressed by both the hematopoietic stem and progenitor cells and the surrounding microenvironments. Knowledge of these molecules is important since many of the genes involved in normal hematopoiesis are mutated in leukemia. Furthermore, this information can be utilized in more efficient isolation and expansion of hematopoietic cells in vitro. However, these molecules are not yet sufficiently characterized. Transmembrane immunoglobulin and mucin domain (TIM) genes form a known family of immunoregulators. In mammals, TIM-4 is expressed by antigen presenting cells, while TIM-1, TIM-2 and TIM-3 are expressed by T cells, in which they regulate differentiation of TH cells. The role of TIM molecules in hematopoiesis has not yet been investigated. The aim of this thesis work was to identify and analyze novel molecules involved in embryonic hematopoiesis using chicken and mouse as model organisms. This was carried out by generating a cDNA library of hematopoietic stem and progenitor cells from embryonic chicken para-aortic region. Both previously known and novel candidate genes were identified from the library. Among them, we found homologs to tim genes. Their expression and role in hematopoiesis was studied further. TIM-2 expression was shown to be tightly governed during B cell development. It is expressed by common lymphoid progenitors and highly proliferative large-pro and large pre-B cells during both fetal liver and adult bone marrow hematopoiesis. In mouse, tim-4 expression was restricted to fetal liver CD45+F4/80+ cells. Furthermore, two distinct populations were identified: F4/80hiTIM-4hi and F4/80loTIM-4lo. The results suggest that the F4/80hiTIM-4hi cells are yolk sac-derived macrophages and the F4/80loTIM-4lo cells myeloid progenitors. This work shows for the first time that TIM family molecules are expressed during hematopoiesis. TIM-2- and TIM-4 are expressed by specific cell types during hematopoietic cell development, and in the future they may be utilized as markers in isolation of hematopoietic progenitor cells<br>Tiivistelmä Verisolut eli punasolut, verihiutaleet ja immuunipuolustuksessa tärkeät valkosolut kehittyvät alkion veren kantasoluista prosessissa, joka on kaikissa selkärankaisissa samankaltainen. Veren kanta- ja esisolujen sekä ympäröivän mikroympäristön tuottamat molekyylit säätelevät hematopoieesia eli verisolujen kehitystä. Näiden molekyylien tunteminen on tärkeää, sillä useat normaalia verisolujen kehitystä säätelevät geenit ovat osallisena myös verisyöpien synnyssä. Lisäksi tätä tietoa on mahdollista hyödyntää verisolujen tehokkaammassa eristämisessä ja kasvattamisessa hoitoja varten. Immuunipuolustuksen solut, kuten syöjäsolut eli makrofagit ja T-solut, ilmentävät TIM-molekyylejä (Transmembrane Immunoglobulin and Mucin). Ne toimivat immunologisen vasteen säätelyssä sekä solusyönnissä, mutta niiden roolia verisolujen kehittymisessä ei ole selvitetty aikaisemmin. Tässä väitöstutkimuksessa etsittiin uusia hematopoieesiin vaikuttavia geenejä käyttäen mallieläiminä sekä kanaa että hiirtä. Tutkimuksessa luotiin geenikirjasto kanan alkion para-aortaalisen alueen veren kanta- ja esisoluista. Kirjastosta tunnistettiin useita ennalta tiedettyjä sekä uusia verisolujen kehitykseen vaikuttavia geenejä. Tutkimuksessa analysoitiin tarkemmin kirjastosta löytyneiden TIM-geeniperheen jäsenten ilmentymistä ja roolia verisolujen kehityksessä. Tutkimuksessa osoitettiin, että TIM-2 proteiinin ilmentymistä säädellään tarkasti B-solujen kehityksen aikana. Lymfosyyttien yhteiset esisolut sekä suuret pro-B- ja pre-B-solut ilmentävät TIM-2 proteiinia B-solukehityksen aikana sekä alkion maksassa että aikuisen luuytimessä. Hiiren alkiossa tim-4 geenin ilmentyminen oli rajoittunut maksaan, jossa erottui kaksi erillistä solupopulaatiota: F4/80hiTIM-4hi ja F4/80loTIM-4lo. Tutkimuksen tulokset viittaavat siihen, että maksan F4/80hiTIM-4hi solut ovat ruskuaispussista lähtöisin olevia syöjäsoluja ja F4/80loTIM-4lo solut myeloidisen linjan esisoluja. Tämä tutkimus on ensimmäinen osoitus TIM-molekyylien ilmentymisestä kehittyvissä verisoluissa. Havaitsimme, että TIM-2 ja TIM-4-molekyylejä ekspressoidaan tietyissä soluissa verisolujen erilaistumisen aikana, joten tulevaisuudessa niitä on mahdollista käyttää merkkiproteiineina hematopoieettisten solujen esiasteita eristettäessä
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Kuchenbauer, Florian. "MiRNAs in hematopoiesis and leukemogenesis." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/16752.
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MicroRNAs (miRNAs) have been shown to play important roles in physiological as well as multiple malignant processes including acute myeloid leukemia (AML). In an effort to gain further insight into the role of miRNAs in AML, we have applied the Illumina massively parallel sequencing platform to carry out an in depth analysis of the miRNA transcriptome in a murine leukemia progression model, based on the engineered over-expression of the nucleoporin 98(NUP98)-homeobox HOXD13 fusion gene (ND13), followed by conversion into AML inducing cells upon transduction with the oncogenic collaborator Meis1. Of the over 307 identified miRNA/miRNA* species in both libraries, sequence counts varied between 2 and 136,558, indicating a remarkable expression range. Our finding of extensive sequence variations (isomiRs) for almost all miRNA and miRNA* species adds additional complexity to the miRNA transcriptome. A stringent target prediction analysis coupled with in-vitro target validation revealed the potential for miRNA-mediated release of oncogenes that facilitates leukemic progression from the preleukemic to leukemia inducing state. Besides over 50 putative novel miRNAs, we found a high abundance of miRNA* species, implying a functional role for these. To further elucidate the function of miRNA*s, we took advantage of 9 deep sequencing libraries from a variety of cell lines to determine the most abundant complementary strand of know miRNAs. Comparing miRNA/miRNA* ratios across the miRNA sequence libraries revealed that most ratios remain constant across tissues and species, allowing a novel classification of miRNAs into α-duplexes, miRNAs duplexes with a dominant strand and β-duplexes with both strands being abundant. However, certain ratios were highly variable across the libraries examined as exemplified for the ratio of miR-223/miR-223*. Bioinformatics as well as functional analysis revealed a possible supporting function of miR-223* to the differentiating role of miR-223 in normal normal bone marrow as well as AML. Taken together, by using deep sequencing we provided deep insight into the changes of the miRNA transcriptome in the development of AML. Furthermore, we propose a new classification for miRNA duplexes and provide evidence for a possible role a miRNA* in the development of acute myeloid leukemia.
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Hysenaj, Lisiena. "Alterations of hematopoiesis during brucellosis." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0251.
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La brucellose est une maladie qui se transmet de l’animal à l’homme. Elle est causée par la bactérie Brucella. Lors de ma thèse, j’ai montré que Brucella persiste dans les cellules de la moelle osseuse des animaux infectés. Ces observations sont très importantes car la moelle est un organe responsable de la génération des cellules du système immunitaires et c’est la principale niche des cellules souches hématopoïétiques. Au cours de ma thèse, j'ai montré que la protéine de la membrane externe 25 de Brucella (Omp25) est capable de lier au récepteur SLAMF1, une molécule exprimée par les cellules souches hématopoïétiques. Cette interaction conduit à la génération d'un plus grand nombre de cellules myéloïdes par les cellules souches hématopoïétiques. Les cellules myéloïdes sont la niche préférée de Brucella. Ainsi, cette stratégie permet à la bactérie d'envahir l’hôte et d'établir une infection chronique de longue durée. SLAMF 1 apparaît comme une nouvelle cible thérapeutique pour le contrôle des maladies infectieuses chroniques, ce qui représenterait une avancée importante dans la génération de nouveaux médicaments<br>Brucellosis is a disease that is transmitted from animals to humans. It is caused by the pathogenic bacterium Brucella. During my thesis, I showed that Brucella persists in the bone marrow cells of infected animals. These observations are very important because the bone marrow is an organ of the immune system responsible for the generation of the immune cells, as it is the principal niche of hematopoietic stem cells. During my thesis, I showed that Brucella outer membrane 25 (Omp25) is able to bind SLAMF1, a hematopoietic stem cell molecule. This interaction leads to the production of more myeloid cells by the hematopoietic stem cell. Myeloid cells are the favorite niche of Brucella. Thus, this strategy allows the bacteria to invade the host and establish a long lasting chronic infection. SLAMF 1 appears as a new therapeutic target for controlling chronic infectious diseases, which would represent an important advance in the generation of new drugs
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Bilotkach, Kateryna. "Quest for early hematopoietic stem cell precursors." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33056.
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The first transplantable hematopoietic stem cells (HSC) arise in the aorta-gonad mesonephros region (AGM) during early stages of embryo development. Specifically, ventral aspect of embryonic dorsal aorta (DA) contains HSC that upon transplantation into irradiated recipients can reconstitute all lineages of the haematopoietic system [Medvinsky et al. 1993; Muller and Medvinsky, 1994; Medvinsky and Dzierzak, 1996; Cumano et al., 1996; Tavian et al., 1996; Peault and Tavian, 2003; Taoudi and Medvinsky, 2007; Ivanovs et al., 2011, 2014]. The ventral aspect of DA bears so-called intra-aortic cell clusters (IAC), the appearance of which coincides with the emergence of HSC [Babovic and Eaves, 2014; Bhatia, 2007; Boisset et al., 2010, 2011; Bollerot et al., 2005; de Bruijin et al., 2002; Bertrand et al., 2010]. According to recent reports, HSC are a heterogeneous population of cells [Dykstra et al., 2007; Seita and Weissman, 2010; Muller-Sieburg et al., 2012]. It is unclear whether all HSC precursors originate from the same location, for example, DA lining, IAC or sub-aortic tissues; or HSC precursors migrate into DA lining from other parts of the embryo [Tavian et al., 1999; Yoder et al., 1997; Oberlin et al., 2002; Peault and Tavian, 2003; Dzierzak, 2003; Samokhvalov et al., 2007; Medvinsky et al., 2011]. To elucidate ontogeny of early HSC precursors (pro-HSC), two approaches were applied in this PhD project. First, we mapped potential pro-HSC in pre-circulation mouse embryos (embryonic day 6-8.5, E6-E8.5). We defined potential pro-HSC as cells co-expressing the transcription factor Runx1, endothelial markers (VE-Cad or CD31) and/or haematopoietic markers (CD45, CD41) [Oberlin et al., 2002; de Bruijn and Dzierzak, 2012; Liakhovitskaia et al., 2009, 2014]. In E6-E8 mouse embryo, prospective pro-HSC were found to be located in chorionic plate, yolk sac and in allantoic core domain. In early somitic mouse embryo (E8-8.5) cells with pro-HSC phenotype (Runx1+CD31+CD41+) were found to be in cell clusters in forming vessel of confluence and in nascent dorsal aortae lining. Pro-HSC are not directly transplantable [Cumano et al., 1996., 2001; Godin et al., 1993; 1995; Batta et al., 2016; Matsuoka et al., 2001; Nishikawa et al., 1998]. Therefore, cells and tissues containing prospective pro-HSC were initially matured using several in-vitro culture systems. According to our results, E8 mouse embryo pro-HSC are only preserved in explant cultures, but not in co-aggregate cultures with stroma cells. After culture, cells were transplanted into sub-lethally irradiated recipients. Six weeks after transplantation 19 out of 82 transplanted recipients had donor derived blood cells' chimerism at the level of 0.1-0.3%. Forty six percent of these grafts were derived from rostral part of the embryo tissues (head, heart, upper somites). Only one out of 82 recipients had donor cells contribution above 1% (1.2 %). This recipient was engrafted with cells derived from the E8 mouse embryo head and heart region. Recipients having blood chimerism at the range of 0.1-0.3% had mainly lymphoid donor derived cells in their peripheral blood. The only recipient showing the high donor cells contribution (1.2%) had contribution mainly to myeloid lineage. Recorded low levels of blood chimersims are in line with those reported by Rybtsov et al. (2014) for early E9 mouse embryos. Donor derived cells formed clearly distinguishable populations on cytometry plots. This population of cells were absent from control engraftment experiments with carrier cells only. Previously, lymphoid potential was detected in paraaortic spnanchnopleura (P-Sp) of E8.5-9 mouse embryos, but not in E8 mouse embryos (0-5 somites, pre-circulation) and later in yolk sac [Cumano et al., 1996; Nishikawa et al., 1998; Fraser et al., 2002; Yokota et al., 2006]. However, prior works used different criteria to establish recipient reconstitution. Therefore, it is possible that recipients repopulated with E8 derived cells at the level of 0.1% were not considered as repopulated and hence, presence of lymphoid lineage precursors was overlooked in early somitic mouse embryos. The only recipient showing substantial myeloid cells contribution (73% Mac1+Gr1+ cells of donor derived cells) received engrafted cells from an older (6-13 sp) embryo and therefore potentially has yolk sac derived myeloid cells. Yolk sac cell contribution to myeloid lineage, specifically to the brain microglia was reported in prior works [Samokhvalov et al., 2007]. Our data show that early E8 AGM cells do not expand in in vitro conditions. While in AGM, cells from E9 mouse embryo expand in culture [Rybtsov et al., 2014]. We have analysed Runx1 expression pattern and dorsal aorta morphology at the time when E9 HSC precursors acquire ability to expand in in vitro culture. Runx1 expression becomes clearly polarised at the time point (22-26 sp), when paired dorsal aortae fusion is initiated. We envision that intimate connection between DA fusion events and induction of pro-HSC maturation exists. According to prior reports, Bmp, Shh and VEGF signalling regulate DA fusion [Garriock et al., 2010]. Thereofore, to enhance in vitro HSC maturation system, DA fusion triggers (for example, Bmp4) might be added to culture. Since, pro-HSC maturation methods established to date are not efficient to expand and differentiate E8 pro-HSC into potent HSC, another approach had to be implemented to study HSC ontogeny. The second approach we utilized was to trace the origin of HSC in chicken embryo, starting from the very beginning of cell fate specification, i.e. from gastrulation stages. Chick embryo haematopoiesis is similar in both human and mouse: precursors of HSC arise in the embryo proper in AGM, and IAC are formed in DA ventral aspect [Dieterlen-Lièvre, 1975; Dieterlen-Lièvre and Martin, 1981; Dieterlen-Lièvre and Jaffredo, 2009; Jaffredo et al., 2000; Le Douarin and Dieterlen-Lièvre, 2013]. In contrast to mammals, chick embryo develops ex vivo, making direct labelling and cell tracing possible. We aimed to identify cells giving rise to regions of DA that produce IAC. Therefore, segments of primitive streak (PS) were labelled with lipophilic dyes or by substituting segments of host PS with PS sections derived from transgenic (GFP+) stage matched chicken embryos. Our results show that in an 18-25h chicken embryo (Hamburger and Hamilton developmental stage 4-6, HH4-6) cells giving rise to DA ingress through the wide region of PS (35-60% of its length) [Hamburger and Hamilton, 1951]. We identified that the section of DA producing HSC is formed by cells ingressing through PS in region of 40-55% of its length at 18-25h of chick embryo development. Regardless of the embryo development stage (HH4-6), in chimeras grafted at 40-55% of PS length, GFP+ cells contributed to DA and to the IAC. Within GFP+ labelled areas, we observed clusters consisting entirely of GFP+ and clusters having a mixture of GFP+ and GFP- cells. Entirely GFP+ clusters were found in the stretch of DA that had the entire aortic endothelial lining labelled. Clusters formed on the mosaic (GFP+/GFP-) aortic endothelium also had mosaic nature. According to our data, multiple descendants of PS contribute to the same stretch of dorsal aorta. This explains mosaicity of dorsal aorta lining and IAC labelling. Since we encountered clusters with mixture of GFP+ and GFP- cells, we conclude that IAC are not clonal formations. Mosaicity of IAC also does not exclude a scenario when cells migrate in and out of a cluster. Further tracing experiments are required to establish HSC nature of cells within a cluster.
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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.
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Huang, Hsuan-Ting. "Epigenetic Regulation of Hematopoiesis in Zebrafish." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10175.
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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.
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Liu, Jianing. "Molecular Modulators of Hematopoiesis and Leukemogenesis." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10206.
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Hematopoietic stem and progenitor cells proliferate and differentiate to reconstitute all lineages of functional blood cells. They are regulated by intricate cellular and molecular signals, on both genetic and epigenetic levels. Alterations in these regulatory signaling networks can lead to hematopoietic dysfunction, as well as transformation of hematopoietic cells and induction of leukemogenesis. This thesis focuses on uncovering molecular modulators that are crucial for the proper regulation of hematopoietic stem/progenitor cells. In Chapter II, I describe studies investigating functional roles of the histone demethylase UTX in normal and malignant hematopoiesis, using a short hairpin RNA-mediated knockdown approach. My data revealed that UTX is required for proliferation, self-renewal and differentiation of hematopoietic progenitor cells ex vivo through transcriptional regulation of hematopoiesis- specific transcriptional factors. I also discovered that UTX is critical for the proliferation of leukemia cells, implicating UTX as a possible target for clinical therapy. In Chapter III, I focus on understanding the process of leukemogenesis by generating and characterizing a novel model of myeloid sarcoma and acute myeloid leukemia in mice. This model induces these hematopoietic malignancies by introduction of multiple oncogenetic lesions (specifically, p16/p19-/-;Kras(G12V)) into bone marrow cells, and subsequent transplantation of these gene-modified cells into immunodeficient NOD.SCID mice. This model is very rapid and reproducible, and represents the first transplantable myeloid sarcoma model reported. Moreover, the disease induced in mice recapitulates the pathological progression of myeloid sarcoma in patients, providing a powerful model for dissection of critical leukemogenic events and discovery of new candidate therapeutic targets. Together, these studies help to reveal novel molecular modulators required for normal hematopoiesis, and offer potential animal model and drug target for therapeutic applications.
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Eshghi, Shawdee. "The roll of integrins in hematopoiesis." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/39905.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2007.<br>Includes bibliographical references (p. 113-123).<br>Hematopoietic stem cells (HSCs) hold great promise for the treatment of disease. The rare frequency at which HSCs occur in the bone marrow under homeostatic conditions is a limiting factor in both their study and clinical use. ex vivo expansion of these cells is therefore a necessary step to maximizing their potential. In this thesis I explore the concept that signals from the extracellular matrix can direct differentiation, survival and self-renewal decisions in hematopoietic cells, and thus can provide a foundation for the design of ex vivo expansion strategies. This work is focused on the role integrins, the major class of cell-extracellular matrix adhesion molecules, play in mediating these signals to hematopoietic cells at two developmental stages. In the erythroid lineage, I show that expansion of committed erythroid progenitors is regulated by growth factor and integrin-mediated signals in temporally distinct regimes. I establish a biologically relevant role for [alpha]401 but not [alpha]501 integrins in erythropoiesis and provide evidence that erythroid differentiation and expansion are regulated by separate processes.<br>(cont.) In the study of uncommitted HSCs, I identify several integrin subunits that are differentially expressed on highly purified HSC populations that correlate with long term repopulating ability. One of these subunits, [alpha]2 integrin, specifically mediates adhesion of HSCs to bone marrow extracellular matrix proteins, thereby providing a potential mechanism for stem cell self-renewal. This work establishes that integrin-mediated interactions between hematopoietic cells and the extracellular matrix are dynamic and provide important developmental cues.<br>by Shawdee Eshghi.<br>Ph.D.
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Abraham, Brian J. "Systems biology approaches to understanding hematopoiesis." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12703.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.<br>Understanding gene expression and the regulation thereof that confer cell type-specific (CTS) functionality holds primary importance in devising therapeutics capable of emulating these functions, especially within blood. Hematopoiesis and further differentiation require epigenetic mechanisms to establish and maintain diverse cell identity and function, given constant genomic content. Gene expression and binding of chromatin-associated proteins coincide, and both change during differentiation from hematopoietic stem cells (HSCs) through progenitors with progressively restricted lineage capabilities to terminally differentiated cells.
To understand the CTS expression patterns that underlie hematopoiesis, I investigated transcriptomes from discrete stages of blood progenitors, including human HSCs, B lymphocytes, T lymphocytes, and erythrocyte precursors as well as many stages of mouse T lymphocyte development and differentiation. Here, I identify hundreds of genes and numerous gene networks showing CTS expression. I next contextualize CTS expression within chromatin environments, including modified histones and other DNA-binding factors using genome-wide binding data. Specific histone modifications and chromatin proteins are enriched at the transcription start sites (TSSs) of CTS genes and correlate with expression. Surprisingly, certain chromatin marks remain at these CTS TSSs in other cell types. I show that TSSs of differentiation regulators are bivalently primed in HSCs, and become selectively activated in their specific cell type. I predict enhancers of CTS genes and show that their chromatin profiles act in mediating expression.
To address regulation of epigenetic modifications during differentiation, I analyzed genome-wide binding profiles oftranscription factor GATA3, which (1) determines T cell lineage commitment, (2) is crucial for differentiation ofT lymphocytes into effector cells, and (3) promotes transcription ofmany T subset-specific genes. I show that GATA3 parsimoniously changes binding patterns during differentiation, and binds a core set of genes as well as T-subset-specific sets. Although GATA3 regulates a small percentage of genes in a cell-type-specific manner, histone modifications at a majority of GATA3-bound genes change significantly after Gata3 deletion, implicating GATA3 in regulatory chromatin organization. I further show that GATA3 binding and function may be mediated by co-binding factors in accord with the presence of their target DNA
sequence motifs.
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He, Liang. "Multiple Functions of Cables1 in Hematopoiesis." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS312.
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Cables1 est impliqué dans la régulation du cycle cellulaire et la survie. Par QPCR et western blot, Cables1 est fortement exprimé dans les cellules souches hématopoïétiques (CSH), les progéniteurs, les cellules de la niche médullaire et les mégakaryocytes. En utilisant un modèle de souris Cables1-/-, nous avons démontré que Cables1 est un régulateur clé de la maintenance homéostatique des CSH àl’état basal et sous stress hématopoïétique. Chez les souris jeunes dépourvues de Cables1, les progéniteurs hématopoïétiques sont hyperprolifératifs et ont un avantage compétitif de repeuplement. La surexpression lentivirale et la déplétion par shRNA de la protéine Cables1 ont respectivement entraîné une régulation positive et négative de p21, indiquant que l'effet de Cables1 sur la prolifération des progéniteurs est partiellement médiée par la régulation de p21. Avec l’âge, les souris déficientes en Cables1 présentent des anomalies du nombre de globules blancs accompagnées d'une réduction significative du compartiment CSH associée à une mobilisation accrue des progéniteurs. De plus, les souris Cables1-/-présentent une sensibilité accrue à un agent myélotoxique à l’irradiation due à des défauts dumicroenvironnement médullaire. Dans les mégacaryocytes, la diminution de Cables1 par shRNA entraîne un défaut de prolifération et unediminution du pourcentage de MK matures. De plus, un défaut de la capacité de formation de proplaquette a été observé après la diminution de Cables1. Ces effets peuvent s’expliquer par une apoptose accrue. En conclusion, Cables1 régule à la fois les progéniteurs et la mégacaryopoïèse. Cables1 donc est essentiel pour l'homéostasie des CSH et le contrôle du stress des CSH. La manipulation del’expression de Cables1 pourrait représenter une opportunité pour optimiser les schémas de chimiothérapie<br>Cables1 has been described to be involved in cell cycle regulation and survival. Using QPCR and western blot, we demonstrate for the first time that Cables1 in highly expressed in hematopoietic stem cells, in niche cells and megakaryocytes. Using the Cables1-/- mouse model, we demonstrate that Cables1 is a key regulator of homeostatic HSC maintenance and under hematopoietic stress. Young mice lacking Cables1 showed hyper proliferation within the hematopoietic progenitor and stem cell (HSPC) compartment. Loss ofCables1 conferred increased competitive repopulating capacity to the HSPCs. Lentiviral mediated overexpression and shRNA mediated depletion of Cables1 protein resulted in p21 up and down regulation, respectively, indicating that the effect of Cables1 on HSPC proliferation is partially mediated through regulating p21. By 1,5 to 2 years of age, Cables1 deficient mice displayed anomalies in whiteblood cell counts accompanied by a significant a reduction in the HSC compartment coupled with increased mobilization of HPC. In addition, Cables1-/- mice displayed increased sensitivity to myelotoxic agent and irradiation. These defects are related to abnormal microenvironment. We also investigated Cables1 function during megakaryopoiesis. Down regulation of Cables1 in CD41+CD42- megakaryocytic progenitors resulted in proliferative defect and decreased percentage of mature MKs, which were accompanied by p21(cyclin dependent kinase inhibitor) and Bax (an apoptosis related gene) up-regulation. Moreover, defect of proplatelet forming capacity was observed after Cables1 knockdown, which can also be explained by elevated apoptosis induced by Bax protein. In conclusion, Cables1 regulate both HSPCs and the process of megakaryopoiesis. It represents a opportunities to optimize chemotherapy schemes
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Cheng, Yi-Han. "The development of surrogate marker-tagged ES cell technology to study haematopoietic commitment." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607864.
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Merino, Juan Jiménez. "Circulatory stem cells of Styela plicata (Lesueur, 1823) (Tunicata: Stelidae): an evolutionary approach." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/41/41133/tde-18022019-090152/.
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Styelid ascidians are diverse in developmental modes, varying from strictly sexual solitary species to highly integrated colonies. Circulatory stem cells (CSCs) accomplish fundamental roles in developmental processes of styelid ascidians. In the colonial styelids, CSCs enable budding and are capable of giving origin to the germline in certain species. The function of these cells have been tested experimentally in models within Styelidae. However, the understanding of coloniality as an evolutionary novelty requires reconstructing the possible ancestral CSCs characteristics in Styelidae. To address this issue, this work analyzes the possible developmental origin and the identity of putative CSCs among blood cell populations. The first chapter of this dissertation aimed to characterize and compare the hemocyte populations in two solitary styelids: Styela plicata and Styela canopus. In addition, the early development, the metamorphosis and the early maturation were compared in both species. After metamorphosis, S. canopus briefly develops a network of extracorporeal vessels with numerous terminal ampullae. These characters are usually associated to colonial ascidians, and were not found in S. plicata. With respect to the hemocyte populations, similar morphotypes were present in both species. However, S. canopus shows a lower frequency of vacuolated cells, which may be due to a reduced level of cytotoxicity in the tunic relative to S. plicata. These differences observed between S. canopus and S. plicata may be related to differences in the degrees of gregariousness or body size among the two species. In order to investigate possible approaches to distinguish and isolate CSC populations in a solitary styelid model, I used imaging flow cytometry. Putative CSCs were identified through measurement of morphological parameters and aldehyde dehydrogenase (ALDH) activity. The correlation between these parameters allowed to determine 2 gates enriched with particular cell types. A significant difference was found on the ALDH+ population within a gate of cells with low granularity, suggesting the presence of cells among circulatory hemocytes. To scrutinize the biogenesis of CSCs in S. plicata, I present a description of a candidate hematopoietic niche in this species. An exhaustive histological survey for hemoblast-like cells was performed, and complemented with immunohistochemistry with stem cell (piwi) and proliferation (pHH3) markers. The morphological and expression profiles of the intestine support the intestinal submucosa (IS) as a hematopoietic niche. At this region there are aggregations of cells with and undifferentiated morphological profile, corroborated by ultrastructural analysis. Furthermore, the IS holds high cellular proliferation and frequency of piwi+ cells. Ascidians are considered interesting models to investigate asexual reproduction and modular development. This study represents an advancement towards understanding the processes, cell populations and structures that may be related to facilitating the appearance of this evolutionary novelty<br>As ascídias da família Styelidae são diversas em modos de desenvolvimento, variando de espécies estritamente sexuais solitárias até colônias altamente integradas. As células-tronco circulatórias (CTCs) desempenham papéis fundamentais nos processos do desenvolvimento de ascídias styelídeas. Nas especies coloniais deste grupo, as CTCs permitem a brotação e são capazes de originar a linha germinativa em certas espécies. A função dessas células tem sido testada experimentalmente em modelos dentro de Styelidae. No entanto, a compreensão da colonialidade como uma novidade evolutiva requer reconstruir as características das possíveis CTCs ancestrais para Styelidae. Com o fim de abordar essa questão, este trabalho analisa a possível origem do desenvolvimento e a identidade de CSCs putativas entre populações de células sanguíneas de styelídeas solitárias. O primeiro capítulo desta dissertação teve como objetivo caracterizar e comparar as populações de hemócitos em dois espécies solitárias: Styela plicata e Styela canopos. Além disso, o desenvolvimento inicial, a metamorfose e a maturação do juvenil foram comparados em ambas as espécies. Após a metamorfose, S. canopus desenvolve brevemente uma rede de vasos extracorpóreos com numerosas ampolas terminais. Esses caracteres são geralmente associados a ascídias coloniais e não foram encontrados em S. plicata. Com relação às populações de hemócitos, morfotipos semelhantes estavam presentes em ambas as espécies. No entanto, o S. canopos apresenta menor frequência de células vacuoladas, o que pode ser devido a um nível reduzido de citotoxicidade na túnica em relação a S. plicata. Essas diferenças observadas entre S. canopos e S. plicata podem estar relacionadas a diferenças nos graus de gregariedade ou tamanho corporal entre as duas espécies. A fim de investigar possíveis abordagens para distinguir e isolar populações de CTCs em um modelo de styelídeo solitário, usei citometria de fluxo com adquisição de imagem. As CTCs putativas foram identificadas através da medição de parâmetros morfológicos e da atividade da aldeído desidrogenase (ALDH). A correlação entre estes parâmetros permitiu determinar 2 gates enriquecidos com tipos celuláres particulares. Uma diferença significativa foi encontrada na população ALDH+ dentro de um gate de células com baixa granularidade, sugerindo a presença de células-tronco circulatórias. Para examinar a biogênese das CTCs em S. plicata, foi realizada uma descrição de um nicho hematopoiético candidato nesta espécie. Um exame histológico exaustivo para células semelhantes a hemoblastos foi realizado e complementado com imunohistoquímica com marcadores de células-tronco (piwi) e proliferação (pHH3). Os perfis morfológicos e de expressão do intestino sustentam a submucosa intestinal (SI) como nicho hematopoiético. Nesta região há agregações de células com morfolia indiferenciada, corroborada pela análise ultraestrutural. Além disso, a SI mantém alta proliferação celular e freqüência de células piwi+. As ascídias são consideradas modelos interessantes para investigar a reprodução assexuada e o desenvolvimento modular. Este estudo representa um avanço na compreensão dos processos, populações celulares e estruturas que podem estar relacionadas a facilitar o surgimento desta novidade evolutiva
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Imai, Takahiko. "Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long-term hematopoiesis." Kyoto University, 2019. http://hdl.handle.net/2433/243275.
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Dodson, Sarah Vanessa Meads. "Hematotoxicity of heptachlor." Morgantown, W. Va. : [West Virginia University Libraries], 2004. https://etd.wvu.edu/etd/controller.jsp?moduleName=documentdata&jsp%5FetdId=3799.
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Thesis (Ph. D.)--West Virginia University, 2004.<br>Title from document title page. Document formatted into pages; contains xi, 196 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.
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Ullrich, Sebastian 1984. "Alternative mechanisms of gene regulation during hematopoiesis." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/665801.
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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.<br>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.
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Brooke-Bisschop, Travis. "The Role of Cdx in Primitive Hematopoiesis." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31580.
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Functional overlap and peri-implantation lethality have made the study of the Cdx family of transcription factors a challenging pursuit. Our research group has generated a conditional genetic knockout model that renders the murine embryo effectively Cdx null, allowing us to explore unknown developmental roles of Cdx. Previously uncharacterized hematopoietic defects are evident in these embryos, and with the use of ChIP-seq technology, a number of hematopoietic genes were identified as putative Cdx targets, including Scl, Lyl1, Lmo2, and Meis1. In addition, the chromatin remodeling protein Brg1 was identified from a SILAC-MS screen of potential Cdx2 interactors, and was studied in the context of direct interaction with Cdx2. My studies suggest a critical role for Cdx in primitive hematopoiesis in mice, and indicate that Cdx2 may recruit Brg1 to specific targets to induce transcription of these genes. //
L'étude des facteurs de transcription Cdx est difficile principalement à cause de la létalité péri-implantation de la perte de Cdx, ainsi que ces facteurs partagent plusieurs fonctions. Notre groupe a généré un modèle de KO génétique conditionnel qui rend l'embryon murin efficacement Cdx nul, ce qui nous permet d'explorer les rôles de développement inconnus de Cdx. Précisément, on a vu des défaits hématopoïétiques dans ces embryons, et avec l'utilisation de la technologie « ChIP-seq », un certain nombre de gènes hématopoïétiques ont été identifiés comme gènes cibles de Cdx putatifs, dont Scl, Lyl1, Lmo2, et Meis1. En outre, on a identifié Brg1, un protéine de remodelage de la chromatine, à partir d'un écran SILAC-MS de interacteurs Cdx2 potentiels. Dans ce regard, on a étudié interaction directe entre Cdx2 et Brg1. Mes études suggèrent un rôle critique pour Cdx dans l'hématopoïèse primitive chez la souris, et indiquent que Cdx2 peut recruter Brg1 à des cibles spécifiques pour induire la transcription de ces gènes.
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Meng, Ronghua Pinkert Carl A. "Molecular mechanisms associated with canine cyclic hematopoiesis." Auburn, Ala, 2008. http://repo.lib.auburn.edu/EtdRoot/2008/SPRING/Biomedical_Sciences/Dissertation/Meng_Ronghua_9.pdf.
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Jordan, Stefan. "Modulation of extramedullary hematopoiesis during cytomegalovirus infection." Diss., Ludwig-Maximilians-Universität München, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-177107.
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Watson, Alexander Scarth. "Autophagy in hematopoiesis and acute myeloid leukemia." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:2e66c5c3-4774-44d1-8345-d0dc827da16d.
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Acute myeloid leukemia (AML) develops following oncogenic alterations to hematopoietic stem (HSC) and progenitor cells (HSPCs) in the bone marrow, resulting in dysregulated proliferation of immature myeloid progenitors that interferes with normal hematopoiesis. Understanding the mechanisms of HSPC protection against damage and excessive division, and how these pathways are altered during leukemic progression, is vital for establishing effective therapies. Here, we show that autophagy, a lysosomal degradation pathway, is increased in HSPCs using a novel imaging flow cytometry autophagy assay. Loss of hematopoietic autophagy following deletion of key gene Atg5 resulted in increased HSC proliferation, leading to HSC exhaustion and bone marrow failure. Although erythrocyte and lymphocyte populations were negatively impacted by autophagy loss, myeloid cells showing immature characteristics were expanded. Deletion of Atg5 in an AML model resulted in increased proliferation under metabolic stress, dependent on the glycolytic pathway, and aberrant upstream mTOR signaling. Moreover, modulation of Atg5 altered leukemic response to culture with stromal cells. Finally, primary AML cells displayed multiple markers of decreased autophagy. These data suggest a role for autophagy in preserving HSC function, partially through suppression of HSPC proliferation, and indicate that decreased autophagy may benefit AML cells. We postulate that modulation of autophagy could help maintain stem cell function, for example during transplantation, and aid AML therapy in a setting-specific manner.
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Gomes, Ana Lúcia da Silva. "Cholestreol influence in normal and malignant hematopoiesis." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/45548.
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Ferrell, Scott A. "ARID3A binding sites and functions in hematopoiesis." Oklahoma City : [s.n.], 2009.
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Gomes, Ana Lúcia da Silva. "Cholestreol influence in normal and malignant hematopoiesis." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/45548.
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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.
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Ding, Xiaolei [Verfasser]. "Polycomb protein Bmi1 in ES cell hematopoiesis and generation of iPSC from Flt3+ hematopoietic stem cells / Xiaolei Ding." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/101818824X/34.
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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.
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Jenkins, Brendan John. "Activating point mutations in the common ?gb?s[beta]-subunit of the human GM-CSF, IL-3 and IL-5 receptors : implications for receptor function and role in disease / by Brendan John Jenkins." Title page, contents and summary only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phj518.pdf.
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Buchrieser, Julian. "Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs)." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:aaf18203-5f30-4d6a-8f51-3096b29af252.
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Tissue-resident macrophages (MΦ) such as microglia, Kupffer and Langerhans cells derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident MΦ self-renew locally, independently of circulating adult monocytes and HSCs. In contrast, adult blood monocytes as well as infiltrating, gut and dermal MΦ derive from Myb-dependent HSCs and are less proliferative. These findings are derived from the mouse, using gene knock-outs and lineage tracing, but their applicability to human development has not been formally demonstrated. Here I use a human pluripotent stem cell (hPSC) differentiation model of hematopoiesis, capable of monocyte/MΦ production over prolonged periods of time, as a tool to investigate human mononuclear phagocyte ontogeny. Using a transcriptomic approach I showed that hiPSC-derived monocytes/MΦ (iPS-Mo/MΦ) produced early in differentiation (first weeks) are more proliferative and less immunologically mature than iPS-Mo/MΦ produced at a later time point. I therefore hypothesised either that iPS-Mo/MΦ only become fully mature after several weeks of differentiation or that there are two developmentally distinct waves of MΦ produced over time. By comparing the transcription profile of iPS-Mo/MΦs to that of primary adult blood monocytes and fetal microglia I then showed that early and late iPS-Mo/MΦs were transcriptionally closer to fetal microglia than to adult blood monocytes. To further investigate if iPS-Mo/MΦs are indeed of the same developmental origin as MYB-independent MΦ such as microglia, I used a CRISPR-Cas9 knock-out strategy to show for the first time, that human iPS-Mo/MΦs develop in a MYB-independent, RUNX1 and SPI1 (PU.1)-dependent fashion. This result makes human iPS-Mo/MΦs developmentally related to, and a good model for, MYB-independent tissue-resident \Macros such as alveolar and kidney MΦs, microglia, Kupffer and Langerhans cells. Interestingly, while MYB was not required for the generation of iPS-Mo/MΦs, its knock-out resulted in an increase in iPS-Mo/MΦ production. To investigate this increase I developed two methods for quantifying the differentiation bottleneck occurring during hiPSC differentiation to iPS-Mo/MΦs. Those techniques highlighted a potential increase in progenitor cell generation in MYB KO cells and thus lay foundation to improve our technical understanding of EB differentiation and will enable enhanced manipulation of the EB model.
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Guiu, Sagarra Jordi 1983. "Notch activation and downstream targets in embryonic hematopoiesis." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/98475.
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La regió de l’aorta-gonada-mesonefros (AGM) és el primer nínxol de les
cèl·lules mare hematopoètiques. Està descrit que la via de Notch és necessària
per generar artèries i cèl·lules mare hematopoètiques. Les cèl·lules mare
hematopoètiques es generen a partir de les artèries durant el desenvolupament
embrionari. Tenint en compte que els vasos arterials es formen abans que les
cèl·lules mare hematopoètiques, durant molt temps ha estat controvertit si la via
de Notch només indueix la formació d’artèries i en canvi l’abscència de cèl·lules
mare hematopoètiques és un efecte secundari o si per contra, la via de Notch
participa activament en la inducció d’ambdós programes genètics, l’arterial i
l’hematopoètic. Moltes de les funcions descrites de la via de Notch són
conseqüència de l’expressió de les seves dianes transcripcionals: Hes i Hesrelated
(Hrt). No obstant cada cop s’estan identificant noves dianes
transcripcionals de la via de Notch que són específiques de teixit.
En aquesta tesis doctoral, demostrem que l’activació de la via de Notch per part
del lligand Jagged1 és necessària per activar el programa hematopoètic però
no cal per establir el programa arterial. Aquest fet demostra que la via de Notch
juga un paper clau i directe en l’hematopoèsi embrionaria. Per sota de la via de
Notch mostrem que els embrions deficients en Hes1 i Hes5 mantenen intacte el
programa arterial. Cal remarcar que també generen més quantitat de cèl·lules
mare hematopoètiques però que no són funcionals. A més tal mutants, tenen
nivells més alts d’expressió dels gens Runx1, Myb i Gata2; els quals són
importants reguladors de l’hematopoèsi. Per acabar demostrem que Notch
activa la transcripció de Gata2 i que HES-1 l’inhibeix. Això genera un
Incoherent Feed-Fordward loop, el qual regula estretament els nivells de Gata2
necessàris per generar cèl·lules mare hematopoètiques.<br>The aorta-gonad-mesonephros (AGM) is the first Hematopoietic Stem Cell
(HSC) niche. It was previously shown that Notch pathway is required to induce
the arterial fate as well as to generate Hematopoietic Stem Cells. HSC emerge
at the site of arterial vessels during embryonic development. Since arterial fate
precedes HSC generation, it has long been controversial whether Notch
exclusively induces the arterial program and the lack of HSC is a secondary
defect; or Notch is directly involved in activating both genetic programs, arterial
and hematopoietic. The best-characterized Notch targets are Hes and Hesrelated
genes (Hrt) since they are involved in most of described Notch
functions, however there is a growing number of tissue-specific transcriptional
Notch-targets.
In this thesis, we found that Jagged-mediated activation of Notch is required for
the correct execution of the definitive hematopoietic program but not for the
establishment of the arterial fate, thus demonstrating that Notch exerts a
specific hematopoietic function in the embryo. Downstream of Notch pathway,
we also show that embryos deficient for Hes1 and Hes5 alleles contain an intact
arterial program but produce increased numbers of non-functional
hematopoietic stem cells associated to higher levels of the hematopoietic
regulators Runx1, Myb and Gata2. Moreover, Gata2 transcription is positively
regulated by Notch and negatively controlled by HES-1. This creates an
incoherent feed-forward loop that tightly controls Gata2 levels to generate HSC.
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Kim, Young-A. "Hematopoiesis, Kazal Inhibitors and Crustins in a Crustacean." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7123.
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Tan, Poh Choo. "Role of podocalyxin in hematopoiesis and cell migration." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/2860.
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CD34 and its relatives, Podocalyxin and Endoglycan, comprise of a family of
surface sialomucins expressed by hematopoietic stem/progenitor cells, and vascular
endothelia. Recent data suggest that they serve as either pro- or anti-adhesion molecules
depending on their cellular context and their post-translational modifications. We were
interested in identifying Podocalyxin ligands and their cellular distribution and
understanding the role of these factors in signaling, adhesion and migration. Using both a
lambda phage screen assay and mass spectrometry, we identified the Na⁺/H⁺ exchanger
regulatory factor-i (NHERF-l) as a selective ligand for Podocalyxin and Endoglycan but
not for the closely related CD34. Furthermore, we showed that NHERF-1 is expressed
by all, lineage⁻, Sca-1⁺ and c-kit⁺ (LSK) cells, which are known to express Podocalyxin
and have long-term repopulating characteristics of hematopoietic stem cells. In addition,
upon IL-3 stimulation of a factor dependent cell line (FDC-P 1) these proteins re-localize
and co-localize in an asymmetrical pattern. By using a lentiviral based shRNA system to
silence Podocalyxin and NHERF- i proteins, we observed that migration across stromal
monolayer towards a CXCL12 and SCF gradient is significantly impeded in cells that
lack Podocalyxin but not NHERF-1. Following in vitro stimulation with a combination
of CXCL12 and SCF we observed that Podocalyxin co-associates with CXCR4.
Furthermore, cells lacking Podocalyxin have decreased phospho-AKT, a key signaling
molecule downstream of c-kit and CXCR4 receptors. Taken together, our data supports
the conclusion that Podocalyxin co-association with CXCR4 modulates downstream
signaling to efficiently regulate HSC homing.
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Kardel, Melanie Dawn. "Analysis of hematopoiesis from human pluripotent stem cells." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/33333.
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Human embryonic stem (ES) or induced pluripotent stem (iPS) cells have the potential ability to generate all of the cell types in the body. If their differentiation into relevant cell types of interest can be effectively controlled, they are attractive for developmental studies, disease modelling, drug testing, and advancing regenerative medicine. The generation of hematopoietic cells from human ES/iPS cells has been reported, but is highly variable and often inefficient. My specific objective in this thesis was to more fully characterize the process whereby hematopoietic cells are generated from primitive pluripotent precursors, to understand current limitations, and to design improvements that would increase the yield and reproducibility of hematopoietic cell generation. I first examined the effect of the conditions used to maintain the undifferentiated starting population of ES/iPS cells on their hematopoietic cell differentiation ability. The results showed that the initial maintenance conditions used do have a significant influence on the subsequent number and consistency of hematopoietic cells generated. In addition, I found that this process is separately influenced by optimization of sequentially manipulated (early and late) differentiation steps. Analysis of individual EBs revealed a previously unappreciated heterogeneity of hematopoietic output from single EBs in vitro. Even under the most optimal conditions studied, it was found that the majority of EBs did not generate any hematopoietic colony-forming cells (CFCs). This suggested that only a limited number of the initial ES/iPS cells were contributing to the hematopoietic progenitor cell output under these conditions. To investigate this latter phenomenon further, I developed a lentiviral system to track the subsequent hematopoietic progeny of marked undifferentiated or early differentiating ES/iPS cells. The use of this approach confirmed that few of the starting ES/iPS cells contribute to the hematopoietic output of individual EBs. Together these studies suggest that the genesis of hematopoietic progenitors from pluripotent precursors remains limited by multiple factors. Further studies to characterize cell types intermediate between fully pluripotent cells and those with hematopoietic activity are needed to define more rigorously and optimize the use of this strategy for various medical applications.
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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.
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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-<br>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.
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Taylor, Allison. "Ribosomal Protein Mutations in Hematopoiesis and Zebrafish Development." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10238.
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The focus of this thesis is the role of ribosomal proteins in hematopoiesis and development. Ribosomal proteins are mutated in patients with Diamond Blackfan anemia (DBA). These mutations primarily affect blood tissues, as DBA patients have a macrocytic anemia. We have identified hematopoietic defects in zebrafish with a mutation in ribosomal protein S29 (rps29). \(Rps29^{-/-}\) embryos have defects in hematopoietic stem cell formation, aorta specification, and hemoglobinization. Embryos also have increased numbers of apoptotic cells, and microarray analysis reveals up-regulation of a p53 gene signature. All of the hematopoietic phenotypes are rescued by p53 mutation, demonstrating that p53 activation induced by ribosomal protein knockdown is mediating the \(rps29^{-/-}\) mutant phenotype. In addition, polysome profiles of mutant embryos identify a decrease in 80s monosome and polysome fractions. Preliminary RNA sequencing analysis of the polysome fractions suggested a shift in genes being translated in the mutant. We performed a chemical screen on rps29 embryos. Using embryo morphology and vascular expression patterns as read-outs, 600 compounds of known bioactivity were screened. One compound, A-3, improves embryo morphology, and a structurally related compound, W-7, rescues the vasculature defect. These compounds are calmodulin inhibitors, and A-3 can also rescue the hemoglobin defect in \(rps29^{-/-}\) embryos. To elucidate the compounds’ mechanism of action, A549 and \(CD34^+\) cells with RPS19 knocked down by shRNA were treated with chemical hits. In these cells, calmodulin inhibitors cause a decrease of p21 even with p53 induction. These data support a model where calmodulin inhibition can inhibit the p53 pathway upon ribosomal protein knockdown. In parallel to our zebrafish studies, we generated induced pluripotent stem (iPS) cells from DBA patient fibroblasts as a part of a large-scale collaboration. Three iPS lines are validated, and a total of 27 lines will be generated from patients with mutations in RPS19, RPL5, and RPL11. Testing for defects in blood differentiation and determining the role of p53 in these lines will enable validation of this system as a model of DBA. The iPS lines can subsequently be used for chemical and genetic screening to identify novel DBA pathways and potential therapies.
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Chen, Xiaoyi. "Role of autophagy in normal and malignant hematopoiesis." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1490354914070478.
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Mon, Père Nathaniel. "Statistical biophysics of hematopoiesis and growing cell populations." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/314684.
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Cell populations in the human body form highly complex systems, their behavior driven by countless processes within the cells themselves as well as their interactions with each other and their environment. A mathematical approach to describing their emergent phenomena on the tissue level typically requires abstractions of these underlying systems in order to obtain tractable and interpretable models, which in turn often leads to descriptions involving stochastic processes.In this doctoral thesis two such cellular systems are investigated. The first is the human hematopoietic system: the machinery by which precursor cells of the blood are cultivated and matured in the bone marrow. This process is essential to enable mammalian physiology, from providing oxygen-carrying erythrocytes to ensuring regular upkeep and preservation of the immune system. Obtaining a quantitative understanding of key aspects of this system can provide valuable insights and testable predictions concerning the origin and dynamics of various blood-related diseases, however, in vivo studies of maturing blood cells pose significant challenges and in vitro studies provide only limited predictive power. The system’s hierarchical architecture is on the other hand well fit to the application of mathematical techniques relying only on a few basic assumptions and parameters. This research aims to contribute to two broader questions concerning hematopoiesis, the first being “What is the shape of this system?” and the second “How does it behave?”. Both questions must be answered sufficiently before quantitative models can be developed with enough predictive power to aid in clinical research and applications.The second project stems from questions in oncology concerning the locomotive capabilities of various cancerous cell types, but ultimately poses these in a broader context, attempting to understand cell motion in the context of a growing but spatially restricted population. Drawing from the domain of non-equilibrium statistical mechanics applied to actively moving particles, an important goal is to understand the effects of heightened proliferation on the collective motion.<br>Les populations cellulaires du corps humain forment des systèmes complexes, leur comportement étant déterminé par d'innombrables processus au sein des cellules elles-mêmes ainsi que par leurs interactions entre elles et avec leur environnement. Une approche mathématique de la description de leurs phénomènes émergents au niveau des tissus nécessite généralement l'abstraction de ces systèmes sous-jacents afin d'obtenir des modèles traitables et interprétables, ce qui à son tour conduit souvent à des descriptions impliquant des processus stochastiques. Dans cette thèse de doctorat, deux de ces systèmes cellulaires sont étudiés.Le premier est le système hématopoïétique humain :la machinerie par laquelle les cellules précurseurs du sang sont cultivées et maturées dans la moelle osseuse. Ce processus est essentiel pour permettre la physiologie des mammifères, depuis la fourniture d'érythrocytes porteurs d'oxygène jusqu'à la préservation du système immunitaire. L'obtention d'une compréhension quantitative des aspects clés de ce système peut fournir des informations précieuses et des prévisions vérifiables concernant l'origine et la dynamique de diverses maladies liées au sang. Cependant, les études in vivo de la maturation des cellules sanguines posent des défis importants, et les études in vitro n'offrent qu'un pouvoir prédictif limité. Par ailleurs, l'architecture hiérarchique du système est bien adaptée à l'application de techniques mathématiques reposant uniquement sur quelques hypothèses et paramètres. Cette recherche vise à contribuer à deux questions plus larges concernant l'hématopoïèse, la première étant "Quelle est la forme de ce système" et la seconde "Comment se comporte-t-il ?Ces deux questions doivent recevoir une réponse suffisante avant que des modèles quantitatifs puissent être développés avec un pouvoir prédictif suffisant pour faciliter la recherche clinique et les applications.Le deuxième projet découle de questions en oncologie concernant les capacités locomotrices de divers types de cellules cancéreuses, mais les pose finalement dans un contexte plus large, en essayant de comprendre le mouvement des cellules dans le disposition d'une population croissante mais limitée dans l'espace. En s'appuyant sur le domaine de la mécanique statistique du non-équilibre appliquée aux particules en mouvement actif, un objectif important est de comprendre les effets d'une prolifération accrue sur le mouvement collectif.<br>Celpopulaties in het menselijk lichaam vormen complexe systemen. Het individuele celgedrag wordt gedreven door zowel talloze processen binnenin de cellen zelf, als door interacties met elkaar en hun omgeving. Een wiskundige beschrijving van fenomenen op het niveau van de weefsels vereist abstracties van deze onderliggende systemen om hanteerbare en interpreteerbare modellen te verkrijgen, waarbij vaak stochastische processen betrokken zijn. In dit proefschrift worden twee van dergelijke cellulaire systemen onderzocht. Het eerste is het menselijke hematopoëtische systeem: de machinerie waarmee voorlopercellen van het bloed worden ontwikkeld in het beenmerg. Dit proces is essentieel om de fysiologie van zoogdieren mogelijk te maken, van het leveren van zuurstofdragende rode bloedcellen tot het onderhoud van het immuunsysteem. Het verkrijgen van een kwantitatief inzicht in aspecten van dit systeem kan waardevolle inzichten en testbare voorspellingen opleveren met betrekking tot de oorsprong en de dynamiek van verschillende bloedgerelateerde ziekten. Echter, in vivo studies van ontwikkelende bloedcellen vormen een aanzienlijke uitdaging en in vitro studies leveren slechts een beperkt voorspellend vermogen op. De hiërarchische architectuur van het systeem verleent zich daarentegen handig naar het toepassen van wiskundige technieken op basis van slechts enkele aannames en parameters. Dit onderzoek heeft als doel bij te dragen aan twee bredere vragen met betrekking tot hematopoëse, de eerste zijnde "Wat is de structuur van dit systeem?" en de tweede "Hoe gedraagt het zich?". Beide vragen moeten voldoende worden beantwoord voordat kwantitatieve modellen kunnen worden ontwikkeld met voldoende voorspellende kracht om klinisch onderzoek te kunnen bijstaan.Het tweede project komt voort uit vraagstukken in de oncologie over de motorische capaciteiten van verschillende kankerceltypes, maar plaatst deze uiteindelijk in een bredere context, waarbij getracht wordt de stochastische beweging van cellen te begrijpen in de context van een groeiende maar ruimtelijk beperkte populatie. Uitgaande van het domein van de niet-evenwicht statistische mechanica toegepast op actief bewegende deeltjes, is een belangrijk doel het begrijpen van de effecten van een verhoogde proliferatie op de collectieve beweging.<br>Doctorat en Sciences<br>info:eu-repo/semantics/nonPublished
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Bettigole, Sarah E. "Novel Functions for XBP1 and IRE1α in Hematopoiesis". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17463152.
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The endoplasmic reticulum (ER) is a critical regulator of cellular homeostasis, primarily responsible for handling calcium storage and signaling, lipid synthesis, and the proper glycosylation and folding of nascent transmembrane and secreted proteins. Numerous stimuli such as dysregulated oxidative stress, depletion of calcium stores, hypo- and hyperglycemia, hypoxia, inefficient cellular degradation pathways, and inflammation can disrupt the protein folding capacity of the ER, leading to a condition known as ER stress. The canonical unfolded protein response (UPR) is a three-pronged signaling axis charged with ameliorating ER stress, and is particularly important for the development of highly secretory tissues such as plasma cells, pancreatic acinar cells, and Paneth cells. Here we examine the requirement for the ER stress response transcription factor XBP1 in hematopoiesis, focusing specifically on granulocyte development.
In this study we found that XBP1 is selectively required for the development of the eosinophil lineage, but not for other granulocyte lineages. Targeted hematopoietic ablation of XBP1 or its upstream activator IRE1α using Vav1-Cre conditional knockout mice resulted in complete loss of mature eosinophils and dramatic decrease in Lin-, Sca1-, CD34+, c-Kitlo, IL-5Rα+ eosinophil progenitors without altering neighboring hematopoietic lineages such as basophils and neutrophils. Myeloid and eosinophil progenitors selectively activated XBP1 without induction of parallel canonical ER stress signaling pathways. Through the use of mixed bone marrow chimeras, in vitro bone marrow-derived eosinophil cultures, and eosinophil-selective Cre mouse models, we demonstrated that XBP1 is required after eosinophil lineage commitment in a cell-intrinsic manner to sustain cell viability. RNA-sequencing and bioinformatic analyses of hematopoietic progenitors at different stages of eosinophil differentiation revealed that Xbp1 deficiency reduced the adaptive protein folding capacity of the ER. Upon eosinophil commitment, this vulnerability led to massive defects in post-translational maturation of key granule proteins required for survival, and these unresolvable structural defects fed back to suppress critical aspects of the transcriptional developmental program.
Taken together, we present the first evidence that granulocyte subsets can be distinguished by their differential sensitivities to perturbations in XBP1-mediated secretory pathway functions. Furthermore, this work implicates the IRE1α/XBP1 signaling axis as a potential therapeutic target for eosinophil-mediated diseases.<br>Medical Sciences
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Althoff, Mark J. "Cell polarity in hematopoietic stem cell quiescence, signaling and fate determination." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583999632089058.
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Hogge, Donna Eileen. "Genetic investigations of human hemopoiesis : studies of clonality and gene transfer to hemopoietic progenitors." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27316.
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In most neoplasms malignant change occurs in a single cell which then proliferates. My purpose was to explore methods to study the cell that gives rise to hemopoietic cancer and to investigate the abnormalities at a molecular level.
Cytogenetic analysis of cells from individual hemopoietic colonies revealed that monosomy 7 syndrome, a hematologic disorder of childhood, arises in a primitive cell capable of differentiating down both myeloid and erythroid pathways.
Long-term bone marrow cultures (LTC) from patients with chronic myelogenous leukemia (CML) favor the growth of Philadelphia chromosome (Ph) negative progenitors which, although cytogenetically normal, could have been part of the malignant clone at a stage prior to the development of the Ph. LTC's were initiated with cells from 2 women with CML who were heterozygous for 2 electrophoretically distinct glucose-6-phosphate dehydrogenase (G6PD) enzyme variants. In one patient, 2/11 progenitors were Ph-negative after 4 to 6 weeks in LTC and 4/30 were nonclonal by G6PD enzyme analysis, i.e. the colonies expressed the enzyme not found in the malignant clone. In this case, karyotypically normal cells were truly normal.
Next, gene transfer to human hemopoietic cells was demonstrated using recombinant retrovirus carrying the selectable marker gene, neor. With the K562 human leukemic cell line as targets up to 60% of infected cells became G418 resistant (G418r). Cloned populations of G418r cells showed unique patterns of retroviral integration in K562 DNA. When the target cells were progenitors from normal marrow, CML blood or fetal liver, the highest frequencies of G418r granulocyte-macrophage or large erythroid colonies was 16% and 5% respectively. Experiments infecting bone marrow cells in LTC with neor virus produced up to 2% G418r colonies after as long as 3 weeks in culture. Using v-src virus to infect LTC failed to perturb hemopoiesis, although infection of bone marrow-derived cells in these cultures was documented.
In summary:
1. Unique populations of hemopoietic progenitors can be identified in culture using several genetic markers including chromosomes, G6PD analysis or gene transfer. 2. The feasibility of retroviral-mediated gene transfer for use on human hemopoietic cells has been demonstrated.<br>Medicine, Faculty of<br>Pathology and Laboratory Medicine, Department of<br>Graduate
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Rode, Christina. "Cell type-specific Runx1 enhancer-reporter mouse lines to study hemogenic endothelium." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:49b91ea8-36a3-4bcd-8842-baa1ee31c7b9.
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Hematopoietic stem cells emerge from a specialized subset of endothelial cells in the midgestation mouse aorta. This subset, the so-called hemogenic endothelium (HE), undergoes a morphological and molecular change to a hematopoietic cell type, as part of the endothelial-to- hematopoietic transition (EHT). Previously, lack of specific markers prevented mechanistic studies of HE, as well as studies into its developmental origin. Runx1 is a critical regulator of developmental hematopoiesis and is expressed in all cell intermediates of EHT. Identification of the Runx1 +23 enhancer led to the development of enhancer-reporter tools in order to isolate HE for further analysis. Here, I investigated the cell-type specific activity of another Runx1 enhancer, located 204 kb downstream of the ATG in exon 1. I generated a novel enhancer-reporter mouse line (204GFP) and determined the expression pattern and lineage potential of 204GFP+ cells. It was established that the +204 enhancer marks all HE and part of the HSCs. Hematopoietic progenitor cells, in contrast, were not marked by the 204GFP transgene. Interestingly, the 204GFP reporter also marks part of the Runx1- expressing sub-aortic mesenchyme. To test whether the 204GFP reporter could enrich for HE when combined with a Runx1 +23 enhancer-reporter transgene, I generated and characterized a 23Cherry transgenic mouse line. Expression analysis of aortic endothelial cells marked by both the 204GFP and 23Cherry transgenes using the Fluidigm platform indicated an enrichment of cells with a HE expression signature. This enrichment will facilitate further analysis of the molecular networks active in HE using whole genome expression profiling. The Runx1 enhancer-reporter models are also valuable tools to track the developmental origin of HE, which remains to be established in the mouse embryo. To this end, I mapped the precise spatio-temporal expression pattern of the 23GFP transgene in pre- somitic embryos and established lineage tracing experiments. This provides the basis to revisit fate mapping of the primitive streak to determine the origin(s) of the HE lineage.
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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
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Shen, Ying. "The JAK/STAT pathway in Drosophila hematopoiesis: function and regulatory mechanisms." Ohio : Ohio University, 2007. http://www.ohiolink.edu/etd/view.cgi?ohiou1194628059.
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Hermida, Felipe Pessoa de Melo. "Células progenitoras CD34+ durante a ampliação esplênica na malária experimental de roedores." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-18102007-153435/.
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A malária é uma infecção causada por plasmódios, cujo controle depende do baço, o responsável pelo clareamento dos eritrócitos parasitos. O aumento da parasitemia induz uma ampliação do baço para resolver a infecção, onde participam células precursoras que apresentam CCD34+ na sua superfície. Estudamos a distribuição e a quantidade de células CD34+ em baços de roedores durante malárias de roedores, para compreender sua participação na ampliação do baço e no controle da infecção. Camundongos C57Bl/6j infectados com as cepas AJ e CR de Plasmodium chabaudi, e com a cepa ANKA de Plasmodium berghei, tiveram seus baços removidos e encaminhados para histologia e citometria de fluxo. A distribuição das células CD34+ mostrou-se mais intensa no 4º dia p.i. e menos intensa no 8º dia p.i.. As células CD34+ livres, por citometria de fluxo, surgem com uma onda no 4º dia p.i.. Sua quantidade é similar entre os modelos de P. chabaudi, mas diferente no P. berghei. Neste trabalho, o influxo de células CD34+ no baço não se relaciona com o controle da infecção.<br>Malaria is caused by Plasmodium sp., which control depends on the spleen, responsible for parasite clearing. The increase of parasitemia implies in spleen amplification to control the infection, with participation of CD34+ cells. We studied the distribution and amount of CD34+ cells in spleen during rodent malaria, to define the role of those cells in spleen amplification and infection control. C57Bl/6j mice were infected with strains CR and AJ of Plasmodium chabaudi, and ANKA strain of Plasmodium berghei. The spleen was removed and processed for histology and flow cytometry. Spleen CD34+ cells was increased in 4th day, p.i., and decreases in 8th day p.i. in all models. By flow cytometry, free CD34+ cells appears as a wave in the 4th day p.i.. P. chabaudi models presented the same level of those cells, which was larger in the P. berghei mice. In this work, increase of spleen CD34+ cells do not correlate with infection control.
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Robert, Moreno Alexandre. "Role of Notch/RBPjk signaling pathaway in embryonic hematopoiesis." Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/1055.
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The process that gives rise to all the mature blood cells from the HSCs (Hematopoietic Stem Cells) is known as hematopoiesis. In the adult, hematopoiesis takes place in the bone marrow although the HSCs are likely generated during embryonic life (reviewed in Cumano and Godin, Ann. Rev. Immunol 2007). Mouse embryonic hematopoiesis starts at embryonic day 7-7.5 in the extraembryonic yolk sac, whereas intraembryonic hematopoiesis starts at 9.5 in the aorta surrounded by gonad and mesonephros (a region known as AGM). The current knowledge is that both hematopoietic tissues can generate either pre-HSCs or adult HSCs that will seed the fetal liver by day 12 (that expands the pool of HSCs) and finally, near birth, the bone marrow, which will sustain adult-life hematopoiesis (reviewed in Cumano and Godin, Ann. Rev. Immunol, 2007). The Notch signaling pathway regulates tissue homeostasis and development not only in the embryo but in the adult as well (reviewed in Lai, Development 2007). Notch controls proliferation, differentiation and cell death in a wide variety of tissues including the nervous system, the vascular system and the hematopoietic system. In the latter, Notch has been described to regulate HSC proliferation, cell fate decisions and inhibition/induction of programmed cell death by apoptosis (reviewed in Radtke, Febs Letters 2006). <br/><br/>Our results from the analysis of knock-out mice for some of the members of the Notch signaling pathway such as RBPjk (Oka, Development 1995), Jagged1 (Xue, Hum Mol Genet 1999) and Jagged2 (Jiang, Genes Dev 1998) and the usage of pharmacological inhibitors such as DAPT or L-685, indicate that Notch is dispensable for yolk sac hematopoiesis, although induces cell death by apoptosis in the compartment of erythroid Ter119+ cells generated in this tissue (Robert-Moreno, Leukemia 2007). On the other hand, Notch signaling pathway is required for the generation of hematopoietic progenitors and HSCs in the AGM since directly regulates the expression of the hematopoietic transcription factor GATA2 (Robert-Moreno, Development 2005). Finally, we propose that Notch activation through the ligand Jagged1 (but not Jagged2) is required for the activation of GATA2 expression and the generation and/or amplification of a pool of HSCs with high repopulation ability (Robert-Moreno, manuscript in preparation).<br><i>El procés de generació de cèl.lules sanguínies madures a partir de les cèl.lules mare hemopoètiques o HSCs (de l'anglès Hematopoietic Stem Cells) rep el nom d'hemopoesi. A l'adult, l'hemopoesi ocòrre en el moll de l'òs tot i que es creu que les HSCs es generen durant el desenvolupament embrionari (revisat a Cumano y Godin, Ann. Rev. Immunol 2007). En el ratolí l'hemopoesi embrionària comença a dia 7-7.5 de gestació, en el sac extraembrionari, mentres que a dia 9.5 comença l'hemopoesi intraembrionària en l'aorta rodejada de gònada i mesonefros (regió denominada AGM). Actualment, es creu que ambdós teixits hemopoètics són capaços de generar pre-HSCs o HSCs adultes, que colonitzaran el fetge fetal a dia 12 de gestació (amplificant-se el nombre de HSCs) i finalment, prop del naixement, el moll de l'òs, on donaran lloc als diferents tipus cel.lulars hemopoètics durant la vida adulta (revisat a Cumano y Godin, Ann. Rev. Immunol, 2007). La via de senyalització cel.lular a través del receptor de membrana Notch regula processos d'homeostasi i desenvolupament de teixits, tant en l'embrió com en l'adult (revisat a Lai, Development 2007). La via de Notch controla processos de proliferació, diferenciació i mort cel.lular en teixits tant diferents com el sistema nerviós central, sistema vascular o el sistema hemopoètic. En aquest últim, s'ha descrit funcions de Notch en la proliferació de cèl.lules mare, presa de decisions de destí cel.lular o prevenció i/o inducció de mort cel.lular per apoptosi (revisat a Radtke, Febs Letters 2006). <br/><br/>Els nostres resultats mitjançant l'anàlisi de ratolins mutants en alguns dels components de la via de Notch, com RBPjk (Oka, Development 1995), Jagged1 (Xue, Hum Mol Genet 1999) i Jagged2 (Jiang, Genes Dev 1998) i l'ús d'inhibidors farmacològics de la via de Notch (tals com DAPT i L-685) indiquen que la via de Notch no és indispensable per l'hemopoesi del sac embrionari, tot i que regula l'homeostasi en el compartiment de cèl.lules eritroides Ter119+ que es generen en aquest, mitjançant la inducció de mort cel.lular programada o apoptosi (Robert-Moreno, Leukemia 2007). En canvi, la via de Notch és requerida per la generació de progenitors hemopoètics i HSCs en la regió de l'AGM i demostrem que aquest procés és degut a que Notch1 regula directament l'expressió del factor de transcripció GATA2 en les cèl.lules endotelials de la paret ventral de l'aorta (Robert-Moreno, Development 2005). Finalment, també proposem que l'activació del receptor Notch a través del lligand Jagged1 (però no Jagged2) és necessària per l'activació de l'expressió de GATA2 i la generació i/o amplificació de HSCs amb gran capacitat repobladora (Robert-Moreno, manuscrit en preparació). </i>
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Andrés, Aguayo Luisa de. "The Role of Msi2 in adult and embryonic hematopoiesis." Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/586094.
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The life-long production of blood cells is enabled by hematopoietic stem and progenitor cells (HSPC) residing in the bone marrow. An understanding of the genes that control how HSPCs work to sustain the continued production of blood cells will enable new techniques to expand them for life-saving transplantation therapies. We have used a retroviral integration screen to search for novel genes that regulate hematopoietic stem cell (HSC) function. One of the genes found was Musashi 2 (Msi2), an RNA binding protein that can act as a translational inhibitor. A gene trap mouse model that inactivates the gene shows that Msi2 is more highly expressed in long term (LT) and short term (ST) HSCs as well as in lymphoid myeloid primed progenitors (LMPPs), but much less in intermediate progenitors and mature cells. Mice lacking Msi2 are fully viable up to more than a year but exhibit severe defects in primitive precursors. Cell cycle and gene expression analyses suggest that the main hematopoietic defect in Msi2 defective mice consists in a decreased proliferation capacity of ST-HSCs and LMPPs. Moreover, HSCs lacking Msi2 are severely impaired in competitive repopulation experiments. We further found that Msi2 is expressed during embryo development in the CD41+ cells in the Aorta-Gonada Mesonephros (AGM), most probably corresponding to the earliest emerging HSCs. Also deficient Msi2 embryos have a decrease in the number of fetal liver HSPCs. Lastly, our experiments show that Msi2 deficient HSPCs have a defect in the Wnt and PTEN/PI3K/Akt pathways that could explain the phenotype observed. Altogether, my thesis provides novel insight in to the role and mechanism of action of Musashi-2 in mouse HSPCs.<br>La producción de células sanguíneas a lo largo de toda la vida se lleva a cabo gracias a las células madre hematopoyéticas y células progenitoras (HSPC) que residen en la médula ósea. El estudio de los genes que controlan cómo estas HSPCs trabajan para sostener la producción continua de las células de la sangre permitirán el desarrollo de nuevos protocolos basados en la expansión ‘in vitro’ de estas células para terapias de transplante. Hemos utilizado un cribado basado en el fenómeno de integración retroviral para buscar nuevos genes que regulan la función de células madre hematopoyéticas (HSC). Uno de los genes encontrados fue Musashi 2 (Msi2), una proteína de unión a ARN que puede actuar como un inhibidor de la traducción. El modelo de ratón desarrollado mediante “gene-trap” y que inactiva el gen, muestra que Msi2 está más expresado en HSCs de largo plazo (LT-HSC) y corto plazo (ST-HSC), así como en los progenitores linfoides-mieloides (LMPP), y su expresión disminuye en progenitores intermedios y células maduras. Los ratones deficientes para Msi2 son completamente viables, pero presentan defectos importantes en los precursores primitivos que se agravan con la edad. El análisis de ciclo celular y de expresión génica sugieren que el principal defecto hematopoyético en ratones con esta deficiencia consiste en una disminución de la capacidad de proliferación de ST-HSCs y LMPPs. Además, las HSCs con déficit de Msi2 no son capaces de repoblar la médula ósea cuando se transplantan junto a médula procedente de ratones “wild-type”. También hemos observado que Msi2 se expresa durante el desarrollo del embrión en las células CD41 + de la Aorta-Gonada Mesonefros (AGM), correspondiendo muy probablemente a las HSCs emergentes. Además los embriones deficientes para Msi2 tienen una disminución en el número de HSPC en hígado fetal. Por último, nuestros experimentos muestran que un déficit de Msi2 en las HSPCs provoca un defecto en las vías Wnt y PTEN / PI3K / Akt; esto podría explicar el fenotipo observado en estos ratones. En conjunto, mi tesis proporciona una nueva perspectiva sobre el papel y el mecanismo de acción de Musashi-2 en HSPCs de ratón.
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Ripich, Tatsiana. "The novel function of SWAP-70 in hematopoiesis/erythropoiesis." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2009. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-25509.
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Abstract
SWAP-70 originally identified as a signaling protein exclusively expressed in B-cells has been recently described in other cells of the hematopoietic system, such as mast cells and dendritic cells. Here we describe a novel role of SWAP-70 in hematopoiesis, specifically in regulation of erythropoiesis. SWAP-70 protein expression is detected at the stage of the hematopoietic stem cell (HSC). Its expression persists throughout several stages of multipotent and myeloid progenitors. In erythroid development SWAP-70 is found from early committed to erythroid lineage precursors, burst-forming unit erythroid (BFU-E) and colony-forming unit erythroid (CFU-E); however its expression declines with erythroid maturation and it is lastly detectable at the basophilic erythroblast stage. The protein’s deficiency leads to 3-fold increase in HSC numbers in the bone marrow (BM). The lack of SWAP-70 does not affect intermediate myeloid progenitors and the first erythroid committed progenitor, BFU-E. Hematopoietic tissues (BM and spleen) of Swap-70-/- mice carry 2-times less CFU-Es, thus SWAP-70 appears to be important at this stage. Swap-70-/- mice have the same frequencies of later erythroid progenitors, Ter-119+ erythroblasts, in the BM but fewer in the spleen. BM and splenic Ter-119+ erythroid Swap-70-/- compartment (basophilic, polychromatic and orthochromatic erythroblasts) exhibit an altered profile that is characterized by the delayed maturation of cells at the polychromatic stage. SWAP-70 deficiency is not critical for steady state erythropoiesis and does not influence blood homeostasis. Yet SWAP-70 is essential for proper stress response in conditions of anemia. Swap-70-/- mice have normal steady state hematocrite level but fail to restore it after induced anemia, thus showing sluggish blunted response to erythropoietic stress. In resting conditions Swap-70-/- early erythroid progenitors (CFU-Es) exhibit aberrant preactivation of the integrin VLA-4, which supports homotypic and heterotypic interaction within the erythroid niche, and are hyperadhesive to fibronectin. Similarly, Swap-70-/- basophilic erythroblasts are hyperadhesive to splenic tissue. Based on our data and our initial observations we propose a novel function of SWAP-70 in the c-kit signaling pathway and integrin-mediated, i.e. VLA-4, interactions that are important for HSC and erythroid progenitor maintanence and differentiation. Better understanding of mechanisms governing red blood cell development and homeostasis is of high relevance in the context of treatment of anemia, a very common blood disorder, which leads to a wide range of clinical complications and is the most common cancer-associated morbidity.
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Thorsteinsdottir, Unnur. "Functional analysis of selected Hox homeobox genes in hematopoiesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq25175.pdf.
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