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1
Liu, Yi. „LATEXIN’S ROLE IN REGULATING HEMATOPOIETIC STEM AND PROGENITOR CELLS“. UKnowledge, 2013. http://uknowledge.uky.edu/physiology_etds/11.
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Previous studies in our lab identified a novel gene, latexin (Lxn), that regulates murine hematopoietic stem cells through balancing apoptosis, self-renewal and proliferation. In these dissertation studies, I performed a series of experiments to examine the function of Lxn using a Lxn conventional knockout mouse, and characterize Lxn’s role in the presence of hematopoietic stresses such as ionizing radiation, cytokines induced-mobilization, and hematopoietic malignancy.
The first series of experiments was designed to determine the role of Lxn in hematopoiesis under homeostatic conditions. I found that Lxn-/- mice exhibited hyperproliferative hematopoiesis, a repopulation advantage and elevated self-renewal capacity which was intrinsic to the Lxn-/- hematopoietic cells. Furthermore, I identified a reduction in apoptotic frequency in Lxn-/- hematopoietic progenitors, which may account for the expansion seen in the progenitor population.
In a second series of experiments, I discovered a role of Lxn in the radio-sensitivity of hematopoietic cells. I found that loss of Lxn in mice confers resistance to ionizing radiation. Lxn-/- mice showed rapid hematological recoveries after radiation exposure at the stem and progenitor cell (HSPC) level. The ablation of Lxn hindered irradiation-induced apoptosis which may underlie the radiation resistance through regulating hematopoietic recovery.
In a third series of experiments, I studied the interaction of Lxn-/- stem and progenitor cells with their microenvironment. Using a granulocyte colony-stimulating factor-induced mobilization model, I determined that the ability of HSPCs to mobilize into the bloodstream was significantly increased in Lxn-/- mice. The adhesive properties of hematopoietic cells were compromised in Lxn-/- animals. Gene expression studies on progenitor cells identified cell-to-ECM interactions were down-regulated upon Lxn deletion, implying the enhanced mobilization efficiency of hematopoietic cells from Lxn-/- mice correlated with reduced adhesion of hematopoietic progenitor cells to stroma.
Last, but not least, I performed a series of experiments to study the putative tumor suppressor role of Lxn in hematological malignancy. I found that Lxn expression was down-regulated in primary tumor and tumor cell lines by promoter methylation. Overexpression of Lxn inhibited lymphoma cell growth both in vitro and in vivo. Overexpressed Lxn increased apoptosis frequency by suppressing the expression of several anti-apoptotic genes, and therefore reduced the tumor growth.
2
Traveset, Martínez Laia 1992. „New insights into transcription that preserve hematopoietic stem cell homeostasis“. Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/670105.
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Maintenance of steady-state and stress-adapted hematopoiesis depends on the fitness of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Hematopoietic stem cells (HSCs) can adapt to stress by expanding their numbers and increasing the output of blood cells. This dynamic and highly complex process needs to be fully regulated in order to maintain a balance between the differentiation of HSCs and the need to keep a constant pool of HSCs. However, the molecular machinery in charge of this tight regulation has yet to be fully characterized. HSCs represent a small proportion inside the HSPC compartment, which also includes the immediate progeny of HSCs, the multipotent progenitors (MPP). MPPs are a cell population that retain full lineage potential yet have a limited self-renewal capacity compared to HSC.
In this Thesis we explore a novel mechanism important for the maintenance and protection of HSC function under stress. We have characterized HSC homeostasis and function upon serial transplantation, after myeloablative injury and after a protocol of total body irradiation. We present in vivo results elucidating a new transcription mechanism involved in the maintenance of the viability and self-renewal capacity of HSCs that restrains its differentiation to MPPs, in situations in which the hematopoietic system must keep constant the stem cell reservoir in order to avoid HSC exhaustion.El manteniment de l'hematopoesi en condicions basals i en situacions d’estrès depèn de l'aptitud de les cèl·lules mare i progenitores hematopoètiques (HSPCs) de la medul·la òssia. Les cèl·lules mare hematopoètiques (HSC) són capaces d’adaptar-se a l’estrès mitjançant l'ampliació dels seus nombres i l'augment de la producció de cèl·lules sanguínies. Aquest procés, dinàmic i molt complex, ha d'estar totalment regulat per tal de mantenir un equilibri entre la diferenciació de les HSCs i la necessitat de mantenir un nombre constant de HSCs. No obstant això, la maquinària molecular encarregada d'aquesta regulació no ha estat encara completament caracteritzada. Les HSCs tan sols representen una petita proporció dins del compartiment de HSPCs el qual també inclou la progènie immediata de les HSCs, els progenitors multipotents (MPP). Els MPPs són una població cel·lular que conserva el potencial de llinatge complet, però que presenta una capacitat d'autorenovació limitada en comparació amb les HSCs. En aquesta tesi explorem un nou mecanisme important pel manteniment i la protecció de la funció de les HSCs sota estrès. Hem caracteritzat com la cèl·lula mare hematopoètica funciona després d’un trasplantament en sèrie, després d’una lesió de mielosupressió i després d’un protocol d’irradiació total. Per tant, presentem resultats in vivo que diluciden un nou mecanisme transcripcional implicat en el manteniment de la viabilitat i la capacitat d’autorenovació de les HSC i que restringeix la seva diferenciació cap a MPPs, en situacions en què el sistema hematopoètic ha de mantenir constant el dipòsit de cèl·lules mare per tal d’evitar el seu esgotament.
3
Kollek, Matthias [Verfasser], und Miriam [Akademischer Betreuer] Erlacher. „Improvement of hematopoietic stem cell transplantations by transient apoptosis inhibition in donor stem and progenitor cells“. Freiburg : Universität, 2016. http://d-nb.info/1136263462/34.
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4
Tabayoyong, William Borj. „Engraftment of embryonic stem cell-derived hematopoietic progenitor cells is regulated by natural killer cells“. Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1089.
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Embryonic stem (ES) cells possess the remarkable ability to form cells and tissues from all three germ layers, a characteristic known as pluripotency. In particular, the generation of ES cell-derived hematopoietic cells could serve as an alternate source of hematopoietic stem cells for transplantation in place of bone marrow cells, which are limited by donor availability and high immunogenicity. The advantages of ES cell-derived hematopoietic cells over bone marrow cells include a greater proliferative capacity, which alleviates the problems of donor shortage, and low level expression of MHC antigens, which suggests immune privilege. However, it is unclear whether the immune system is capable of recognizing and rejecting ES cell-derived hematopoietic cells following transplantation. The observation that ES cell-derivatives express low levels of MHC class I, the predominant inhibitory ligand for NK cells, led us to hypothesize that ES cell-derived hematopoietic progenitor cells (HPC) are susceptible to NK cell-mediated killing.
To test this hypothesis, we first generated HPCs from murine ES cells ectopically expressing HOXB4, a homeobox transcription factor that confers hematopoietic self-renewal, and confirmed that HPCs expressed low levels of MHC class I antigens. To specifically investigate the role of NK cells in regulating the in vivo engraftment of HPCs, we transplanted NK-replete Rag2-/- or NK-deficient Rag2-/-γc-/- mice with HPCs. We observed permanent HPC engraftment in Rag2-/-γc-/- mice; however, HPC engraftment was significantly reduced in Rag2-/- mice and was eventually eliminated over time. Bone marrow harvested from these animals showed that HPC-derived Lin-c-kit+ and Lin-Sca-1+ progenitor cells, critical progenitor cells for long-term hematopoietic engraftment, were deleted in Rag2-/- but not in Rag2-/-γc-/- mice.
Next, we focused on the mechanism of NK cell activation by HPCs. Increased expression of the cytotoxic proteins Granzyme B and Perforin in the NK cells of HPC-transplanted Rag2-/- mice confirmed in vivo NK cell activation. Phenotypic analysis of HPCs revealed high level expression of H60, a ligand of the NK activating receptor NKG2D, and neutralization of H60 rescued HPCs from NK cell-mediated killing.
Altogether, our results demonstrate that NK cells are a major barrier to the successful engraftment of ES cell-derived hematopoietic cells, underlining an important role of the innate immune system in regulating the long-term engraftment of ES cell derivatives.
5
Cova, Giovanni. „The role of Helios in the hematopoietic stem and progenitor cell development“. Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ092.
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Les cellules souches et progénitrices hématopoïétiques (CSPH) produisent les cellules sanguines durant toute la vie. Elles sont divisées en cellules souches indifférenciées (CSH) et en cellules progénitrices multipotentes engagées (MPP). Les MPP sont hétérogènes et composées de cellules progénitrices multipotentes engagées vers les lignages érythro-mégacaryocytaires (MPP2), myéloïdes (MPP3) et lymphoïdes (MPP4). Malgré que ces populations cellulaires soient bien définies, les mécanismes moléculaires gouvernants leurs différenciations restent en grande partie encore inconnus. Nous avons montré que le facteur de transcription Hélios, exprimé fortement dans les CSPH, est crucial pour la spécification et le vieillissement des CSPH. Les greffes de moëlle osseuse et les expériences de différenciation ex-vivo et de cytométrie en flux montrent que les souris déficientes pour Hélios possèdent un nombre réduit de MPP4 et de progéniteurs lymphoïdes. Ce déficit est compensé par une augmentation du nombre de MPP3 et de progéniteurs granulo-monocytaires et mégacaryocytaires. De plus l’analyse transcriptionnelle des CSPH indique que la déficience pour Hélios affecte principalement les CSH exprimant des gènes spécifiques aux mégacaryocytes et aux vieilles CSH, tandis que les MPP déficients pour Hélios expriment faiblement les gènes spécifiques aux cellules lymphoïdes. Notre travail montre que Hélios est un nouveau régulateur de la spécification et du vieillissement des HSCHematopoietic Stem and Progenitor Cells (HSPC) engender all the mature blood cells throughout life. They are subdivided in undifferentiated stem cells (HSC) and primed multipotent progenitors (MPP). MPP are heterogeneous and composed of erythro-megakaryocytes (MMP2), myeloid (MPP3) and lymphoid (MPP4) primed cells. Despite the fact that these populations are well defined, the molecular mechanisms underlying their differentiation remain unclear. We showed that the transcription factor Helios, highly expressed in the HSPC, is crucial for HSPC specification and aging. Bone marrow transplantation, ex-vivo differentiation and flow cytometry assays revealed that Helios deficient mice have reduced MPP4 as well as lymphoid progenitors. This deficiency is offset by an increase in MPP3, granulo-monocyte and megakaryocyte progenitors. Moreover,transcriptional analysis of HSPC revealed that Helios deficiency affects mainly HSC with an enrichment of megakaryocyte and old HSC genes signatures, where as Helios deficient MPP express lower levels of lymphoid specific genes. Our work reveals Helios as a novel regulator of HSC specification and aging
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Schütte, Judith. „Analysis of regulatory networks in blood stem/progenitor cells“. Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648631.
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Guthrie, Steven Mitchell. „Hemangioblasts from hematopoietic stem cells to endothelial progenitor cells and their effector molecules /“. [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010068.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 95 pages. Includes Vita. Includes bibliographical references.
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Chen, Inn-Inn. „The role of ephrinB2 in hematopoietic stem/progenitor cell differentiation from an arterial hemogenic endothelium“. Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:3a561742-155f-447e-beb6-42ede41d9bb5.
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During development, hematopoiesis develops in temporally distinct waves in the yolk sac (YS) and embryo proper, culminating in the emergence of definitive hematopoietic stem cells (HSCs) from the hemogenic endothelium (HE) of the dorsal aorta. The close association of this aortic endothelium with definitive hematopoiesis suggests a functional relationship between arteriogenesis and blood development, but this association is not fully understood. To gain insight into this relationship, we have chosen to study the role of the “arterial” marker, EphrinB2 (EfnB2) in hematopoietic specification. EfnB2 is a transmembrane protein critical for the development of the arterial vascular system. We find that EfnB2 is expressed in the VE-Cadh+CD41- HE in Day 2 BL-CFC (blast-colony forming cell) culture and Day 6 EBs (embryoid bodies), and that EfnB2 expression in ES cell differentiation enriches for endothelial cells with greater hemogenic capacity. Knock-down experiments in ES cells showed that EfnB2 is not required for endothelial cell commitment and survival. It is also not required for early hematopoietic commitment and differentiation from EBs or BL-CFCs. However, we find that EfnB2 is required for the maturation of ES cells into CD41+/CD45+ hematopoietic cells in OP9 co-culture and for definitive hematopoietic colony formation in MethoCult3434 medium. This requirement for EfnB2 expression was confirmed by peptide-mediated blocking of EfnB2 binding to its cognate receptors and by forced expression of a phospho-tyrosine signaling-deficient EfnB2. These results provide evidence for an essential role of endothelial EfnB2 in hematopoiesis.
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Eliasson, Pernilla. „Live and Let Die : Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells“. Doctoral thesis, Linköpings universitet, Experimentell hematologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-52932.
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The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.On the day of the defence date the title of article II was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.
10
McBrien, Marie. „The effect of Poly I:C induced inflammation on hematopoietic stem and progenitor cell behaviour in the zebrafish hematopoietic transplant model“. Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/55871.
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Hematopoietic stem cells are a small but significant population of cells fundamental for generating and maintaining the hematopoietic system. These cells are used in the treatment of cancer and auto-immune patients. Studies in mammals suggest that inflammation and infection can modulate the biology of these cells, affecting their location, self-renewal capacity and directing differentiation. The aim of this work was to study the effect of repeated stimulation on the hematopoietic stem and progenitor (HSPCs) population in zebrafish (Danio rerio) to benefit from the live imaging potential of this model organism. It was hypothesised that early post-transplant HSPC behaviour (e.g. lodgement in the niche, self-renewal, mobilisation and differentiation) could be observed and would be indicative of the success or failure of HCT. Double transgenic Tg (cd41:GFP; lysc:dsRed) donors, in which HSPCs express green fluorescent protein (GFP+) and myeloid cells express red fluorescent protein (dsRed+) were used. HSPCs were sorted from donor whole kidney marrow (WKM) and transplanted into irradiated optically-transparent recipients, which were then imaged using wide-field microscopy, individually tracked for survival and hematopoietic reconstitution was assessed after 28 days by flow cytometry. Indeed, initial experiments showed that early observations of cells in the WKM correlated with hematopoietic recovery and survival of recipients, although the strength of the correlation was not sufficiently powerful for predicting recipient outcome. This refinement of the HCT protocol lead to the potentiality of studying the behaviour of HSPCs in the context of inflammation. Inflammation was initiated with repeated intra-peritoneal injections of the viral mimic Polyinosinic:polycytidylic acid (poly I:C) in either the donor or recipient prior to transplant. Poly I:C injection of donors prior to transplant causes HSPCs to colonise the recipient WKM at a greater rate than HSPCs from sham (PBS-injected) donors. However, this did not appear to affect recipient survival or WKM reconstitution at 28 days. Poly I:C injection of recipients prior to transplant did not affect early post-transplant repopulation of the WKM, myelopoiesis, recipient survival, or WKM reconstitution at 28 days. Future work will use competitive transplants to confirm these findings and will explore alternative inflammation models. Furthermore, the confounding factor of irradiation-caused inflammation will be mitigated by transplanting HSPCs into optically-transparent bloodless recipients. Overall, this thesis has demonstrated that the zebrafish can provide valuable in vivo data for studying HSPC behaviour in the recipient post-transplant.
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Bergman, Märta. „Evaluation of an automated method for measuring hematopoietic progenitor cells to determine the start of stem cell apheresis“. Thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-406566.
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Stem cell transplantation is a known treatment for various cancers. Currently most cells transplanted are collected via apheresis. An injection of growth factor is given to the patient to start the proliferation and mobilization of stem cells. Apheresis can be initiated when the patient has a stem cell count of 15 to 20 stem cells/µL of peripheral blood. The standard method with which stem cells are analysed is immune flow cytometry where CD34+ and CD45+ are identified with targeted fluorescent antibodies. This analysis takes more than 45 minutes to perform. Sysmex XN-9000 analyses samples with flow cytometry by lysing erythrocytes and platelets and staining the leukocytes with fluorescent dye. Analysis of the hematopoietic progenitor cells (HPC) takes less than 4 minutes. The purpose of this study was to investigate ifit is possible to predict the start of the apheresis using XN-9000. For this study, 43 samples were analysed using both methods. Using the sign test, a p-value was calculated to <0.05, which indicates a significant difference between the results received by the two methods. Spearman’s rank correlation gave an observed ρ-value > the critical ρ-value which revealed a correlation between the methods, although not linear according to Pearson’s correlation coefficient. PPV and NPV were calculated with cut-off at 20, 30 and 40 HPC/µL blood where 20 HPC/µL gave an NPV at 100 %. According to the test made, there is correlation between the two methods, but further samples must be analysed to investigate how the results should be compared.
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Dahl, Lina. „Stem cell function and organ development : analysis of Lhx2 function in hematopoietic stem cells and eye development“. Doctoral thesis, Umeå universitet, Umeå centrum för molekylär medicin (UCMM), 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-35933.
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When a multicellular organism suffers damages to tissues/organs it heals itself by either substituting the lost cellular matrix by scar formation or by regenerating the lost tissue. Regeneration likely occurs by a recapitulation of the developmental process that formed the organ. Many processes regulating organ development are based on epithelial-mesenchymal interactions and a strict control of organ specific stem/progenitor cells. Elucidation of the molecular basis of these processes is therefore vital in order to develop novel therapies in regenerative medicine. The LIM homebox gene Lhx2 is interesting in this context since Lhx2 has been shown to be important for the formation of several organs by regulating epithelial-mesenchymal interactions and progenitor cell function. Targeted inactivation of Lhx2 leads to a lethal anemia due to malformed liver and severe neural abnormalities such as hypoplasia of the forebrain and anophtalmia. Thus, elucidation of the mechanisms of the function of Lhx2 in different organ systems would give important insights into the molecular mechanisms regulating epithelial-mesenchymal interactions and stem/progenitor cell function. To elucidate the function of Lhx2 in the hematopoietic system Lhx2 was initially expressed in hematopoietic progenitor cells derived from ES cells differentiated in vitro using retroviral vectors. This approach led to the generation of hematopoietic stem cell (HSC)-like cell lines suggesting that Lhx2 could impact HSC function. However neither the specificity nor the efficiency of the Lhx2-induced phenotype could be determined using this approach. To be able to elucidate the function of Lhx2 in the hematopoietic system, an ES cell line with inducible Lhx2 expression was generated. Lhx2 expression induces self-renewal of a distinct hematopoietic progenitor cell from which HSC-like cell lines were established. Down-regulation of Lhx2 in these HSC-like cell lines leads to a rapid loss of stem cell character, providing a good model to study the molecular function of Lhx2 in hematopoietic stem/progenitor cells. A global gene expression analysis was performed comparing the Lhx2+ stem cell population to the Lhx2- differentiated progeny. This approach identified genes putatively linked to self-renewal/differentiation of HSCs. A considerable proportion of the genes showed an overlapping gene expression pattern with Lhx2 expression in tissue of non-hematopoietic origin suggesting that Lhx2 function in stem/progenitor cells partly overlap with Lhx2 function during organ development. In order to define other Lhx2-dependent progenitor cell populations and to generate a tool to analyze the function of Lhx2 in organ development a new transgenic mouse model was generated. By using a specific part of the Lhx2 promoter to drive expression of Cre recombinase in vivo (Lhx2-Cre mice) we have been able to define the first eye committed progenitor cells in the forebrain. By using the Lhx2-Cre mice it will be possible to distinguish the function of genes during eye development from their function in the patterning of the forebrain e.g. the eye field transcription factors. Conditional inactivation of Lhx2 in these eye specific progenitor cells causes an immediate developmental arrest. The transgene is also active in Lhx2-/- embryonic forebrain, but re-expression of Lhx2 in Lhx2-/- progenitor cells only promote formation of retinal pigment epithelium cells. Analysis of genes expressed by the Lhx2+ stem cell population allowed us to define novel genes putatively linked to Lhx2 function in eye development. Thus, we have defined the progenitor cells in the forebrain committed to eye development and the expansion and patterning of these progenitors are dependent on Lhx2. Although commitment to eye development is Lhx2-independent, Lhx2 might be important for the acquisition of the oligopotent fate of these progenitor cells.
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Löffler, Dirk [Verfasser], und Heinrich [Akademischer Betreuer] Leonhardt. „Asymmetric Segregation of lysosomes during hematopoietic stem and progenitor cell divisions / Dirk Löffler ; Betreuer: Heinrich Leonhardt“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1114661236/34.
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14
Ewels, Philip Andrew. „Spatial organisation of proto-oncogenes in human haematopoietic progenitor cells“. Thesis, University of Cambridge, 2013. https://www.repository.cam.ac.uk/handle/1810/245861.
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The eukaryotic cell nucleus is a highly organised organelle, with distinct specialised sub- compartments responsible for specific nuclear functions. Within the context of this functional framework, the genome is organised, allowing contact between specific genomic regions and sub-compartments. Previous work has shown that genes in both cis and trans can make specific contacts with each other. I hypothesise that such a preferred juxtaposition may impact the propensity for specific cancerinitiating chromosomal translocations to occur. In this thesis, I describe how I have extended and developed a ligation based proximity assay known as enriched 4C. I have coupled this technique with high throughput sequencing to determine genomic regions that spatially co-associate with the proto-oncogenes MLL, ABL1 and BCR. In addition to further developing the laboratory protocol, I have created bioinformatics tools used in the analysis of the sequencing data. I find that the association profiles of the three genes show strong correlation to the binding profile of RNA polymerase II and other active marks, suggesting that transcribed genes have a propensity to associate with other transcribed regions of the genome. Each gene also exhibits a unique repertoire of preferred associations with specific regions of the genome. Significantly, I find that the most frequent trans association of BCR is telomeric chromosome 9, encompassing its recurrent translocation partner gene ABL1. Interestingly, ABL1 is not at the maximum point of interaction. I use DNA-fluorescence in-situ hybridisation to validate the e4C association. My data supports a hypothesis that gene transcription has a direct role on genome organisation. I suggest that preferred co-associations of genes at transcription factories may promote the occurrence of specific chromosomal translocations.
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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.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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Diedrich, Beatrice. „Storage and transfusion of platelets in vitro and in vivo studies in healthy volunteers and in allogeneic hematopoetic progenitor cell transplant recipients /“. Stockholm : Karolinska institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-280-6/.
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Patrizia, Marzorati. „Characterisation of Hematopoietic Stem/Progenitor cells and their mobilization in uPAR KO mice“. Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.524734.
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Lin, Shan. „Modeling and Analysis of Acute Leukemia using Human Hematopoietic Stem and Progenitor Cells“. University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1481032144780412.
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Cochonneau, Stéphanie. „Modulating hematopoietic progenitor cell engraftment and T cell differentiation : role of conditioning and route of administration“. Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20226.
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Les déficits lymphocytaires T peuvent être corrigés par l'administration en intraveineuse (IV) de cellules souches hématopoiétiques (CSH) provenant d'un donneur. Dans un modèle d'immunodéficience lié à l'absence de la protéine kinase ZAP-70, notre équipe avait précédemment montré que l'injection intrathymique (IT) de CSH histocompatibles conduit à une reconstitution du compartiment T plus robuste et plus rapide que dans le cas où les CSH sont administrées par voie IV. Au cours de ma thèse, je me suis intéressée à l'approche IT dans un contexte non-histocompatible, où j'ai montré que l'injection de CSH semi-allogéniques directement dans le thymus permet le développement d'une thymopoièse à long-terme, même en absence de conditionnement. De plus, j'ai également montré la persistence de progéniteurs thymiques précoces (ETP) provenant du donneur dans le thymus des souris transplantées. De façon remarquable, ces ETP retiennent un potentiel de différenciation plus divers que ceux rencontrés dans le thymus d'une souris sauvage, et leur fréquence est significativement élévée après IT, ce dernier suggérant une disponibilité accrue des niches thymiques. De façon intéressante, j'ai également montré que les progéniteurs déficients en ZAP-70 pouvaient se différencier de façon importante vers le lignage CD8 lors d'une activation constante de la voie de signalisation Notch couplée à la présence d'interleukine 7 (IL-7). Après la greffe de CSH par voie IV de souris ZAP-70-/-, en absence de conditionnemt, j'ai également identifié l'accumulation d'une population de CSH présentant un phénotype particulier (Lin- Sca 1+ c-kit-), nommée LSAPT. Ces cellules LSAPT présentent un biais de différenciation vers le lignage T γδ ainsi qu'une production élevée d'IL-17, ce qui suggère que les fonctions effectrices d'une cellule T γδ sont dépendantes de leur origine progénitrices. L'ensemble de mes résultats apporte à la fois de nouveaux éléments concernant l'identification de progéniteurs T et démontrent de l'influence/coopération entre voies de signalisation et facteurs environnementaux dans la modulation de la différenciation T et de leur fonctions effectricesT cell deficiencies can be corrected by the intravenous (IV) injection of donor hematopoietic stem cells (HSCs). Using a murine model of ZAP-70-/- deficiency, our group previously showed that the intrathymic (IT) administration of histocompatible HSCs leads to a more robust and long-term thymopoiesis as compared to that achieved by the classical IV route. During my PhD, I found that the direct IT administration of semiallogeneic HSCs results in a sustained donor-derived thymopoiesis, overcoming histocompatibility barriers, even in the absence of conditioning. Furthermore, I found that donor-derived early thymic progenitors (ETPs) persist in the thymi of ZAP-70-/- transplanted mice, and present increased multi-lineage potential as compared to wild-type ETPs. Importantly, the frequency of donor-derived ETPs was augmented following IT transplantation, indicative of an increased progenitor niche. Interestingly, ZAP-70-deficient HSC could themselves be driven to a CD8 lineage fate in an environment where IL-7 potentiates continuous activation of the Notch pathway. Following IV transplantation of donor HSC into non-conditioned ZAP-70-/- mice, I determined that there is an accumulation of lineage-/Sca1+ donor progenitors lacking expression of the stem cell marker c-kit, termed LSAPT. These LSAPT show a biased differentiation towards the γδ T cell lineage with high IL-17-producing effector function, suggesting that progenitor origin regulates γδ T cell fate. The ensemble of my experiments provide new insights into the identity of T lineage progenitors and demonstrate how signaling pathways as well as environmental factors modulate T cell differentiation and effector function
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Xin, Xing. „Effects of polychlorinated biphenyls (PCBs) on telomere maintenance in hematopoietic stem cells and progenitor cells“. Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/2026.
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Polychlorinated biphenyls (PCBs) are synthetic persistent organic compounds that are known to be carcinogenic to humans. Changes in telomerase activity and telomere length are hallmarks of aging and carcinogenesis. Retention of telomerase activity and long telomeres are key characteristics of stem cells and progenitor cells. I hypothesize that PCBs modulate telomerase activity and telomeres of hematopoietic stem cells and progenitor cells via interference of gene regulation and potentially disrupt cell differentiation. To investigate this possibility, I used progenitor-like cells, human promyelocytic leukemia cells (HL-60), and stem cells from rat bone marrow. I show that PCB126 and PCB153 display toxic effects on telomerase activity, telomere length and their related gene expression in progenitor-like HL-60 cells, but they did not exert much effect on differentiation. Further, an in vivo/in vitro study using rat bone marrow cells shows that PCB126-induced hematotoxicity, evidenced by reduction in telomerase activity and TERT gene expression, an increase of the differentiation and a change in the differentiation direction towards granulocytes, which indicate an effect on stem cell function. I also show that the most potent dioxin-like congener, PCB126, regulates hTERT gene expression by activation of the AhR pathway. Both AhR and ARNT work together as a repressor of hTERT transcription. This research improves our understanding of mechanisms of PCB126 and PCB153 toxicity on hematopoietic stem cells and progenitor cells, which will ultimately have significant implications for human health.
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Edling, Charlotte. „Receptor tyrosine kinase c-Kit signalling in hematopoietic progenitor cells“. Doctoral thesis, Umeå : Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-888.
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Yates, Jeffrey Lynn. „THE GENETIC REGULATION OF THE RESPONSE OF HEMATOPOIETIC STEM/PROGENITOR CELLS TO THE CYTOSTATIC AGENT HYDROXYUREA“. UKnowledge, 2006. http://uknowledge.uky.edu/gradschool_diss/420.
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Cellular proliferation is a key characteristic of hematopoietic stem and progenitor cells (HSC/HPCs) that allows for the production of all blood cell lineages during an individuals lifetime. While this feature of stem cells is strictly regulated during steadystate and stress hematopoiesis, it also contributes to the development of myeloproliferative disorders, such as chronic myelogenous leukemia, essential thrombocythemia, and polycythemia vera. It should come as no surprise then, that common treatments for these diseases often target the proliferative nature of the dysfunctional HSC/HPCs. Thus, the identification of molecular determinants of cell cycle regulation associated with these disorders could serve as targets for novel therapies. Using the hematopoietic system of the inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), it was found that the HSC/HPCs of the long-lived B6 mouse strain were less susceptible to the cytostatic agent hydroxyurea (HU) than the short-lived D2 mouse strain. A quantitative trait locus (QTL) analysis revealed a region of proximal chromosome 7 that regulates this response to HU. Congenic mouse strains were generated and phenotypic analysis confirmed that the B6 and D2 loci confer a low and high sensitivity of the HSC/HPCs to HU, respectively. We then showed that while this response of the HSC/HPCs to HU is independent of their cell cycle status, the B6 allele of this QTL confers a proliferative advantage to bone marrow cells after bone marrow transplantation. Having shown that proximal chromosome 7 regulates the response of HSC/HPCs to HU, we found it necessary to characterize the gene and protein expression profiles in order to identify the responsible candidate genes. We first analyzed mRNA expression profiles of HPCs from the parental and congenic mouse strains using gene microarrays and found that four genes within the congenic interval were differentially expressed. Real-time PCR confirmed that the expression profile of only one gene, Ndufa3, is significantly different in HPCs of B6 and D2 mice. Concurrently, we assessed the protein expression profiles of HPC-enriched mononuclear cells. Significant differences were found between the cytoplasmic and nuclear fractions of both strains, with a skewing of protein expression towards the D2 congenic strain.
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Thieme, Sebastian, Sabine Stopp, Martin Bornhäuser, Fernando Ugarte, Manja Wobus, Matthias Kuhn und Sebastian Brenner. „Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells“. Ferrata Storti Foundation, 2013. https://tud.qucosa.de/id/qucosa%3A28908.
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The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact.
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Thieme, Sebastian, Sabine Stopp, Martin Bornhäuser, Fernando Ugarte, Manja Wobus, Matthias Kuhn und Sebastian Brenner. „Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells“. Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-178636.
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The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact.
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Ma, Kuiying. „Regulation of early human T cell development Generation of adult human T-cell progenitors for immunotherapeutic applications TNFα enhances in vitro generation of T-cell precursors from human hematopoietic stem and progenitor cells“. Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB040.
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La première étape du développement lymphocytaire T se caractérise par la migration de progéniteurs hématopoïétiques dans le thymus et l'initiation du programme de différenciation T. La régulation du développement des lymphocytes T est étroitement associée au micro-environnement du thymus. Cependant, en raison de modèles d'étude limités, les mécanismes régulant le développement des lymphocytes T humains sont encore peu compris. Nous avons donc développé un système de culture in vitro sans stroma qui soutient le développement précoce des cellules T humaines à partir de cellules souches / progénitrices hématopoïétiques humaines néonatales et adultes. Ce système est basé sur un composant principal, le ligand de Notch DL-4. Les progéniteurs de cellules T générés dans le système de culture DL-4 présentent des caractéristiques similaires à ceux des thymocytes T immatures humains. De plus, ces cellules ont un potentiel de différenciation T puisqu'ils produisent des lymphocytes T matures avec un répertoire TCR très diversifié après transplantation à des souris NOD/SCID/gamma(c)- / - . Au cours de mon travail de thèse, j'ai optimisé le système de culture en ajoutant du TNFa, une cytokine naturellement exprimée dans le thymus et qui améliore considérablement la génération in vitro de progéniteurs T grâce à une augmentation de la survie et de la prolifération des précurseurs T, ainsi qu'en inhibant la différenciation myéloïde. J'ai également démontré que la régulation du TNFa sur les progéniteurs des lymphocytes T était principalement basée sur l'activation de la signalisation NFkB, ainsi que la régulation de l'expression d'un inhibiteur de l'apoptose. Dans l'ensemble, cette thèse décrit une stratégie basée sur la signalisation Notch et NFkB pour la génération in vitro de progéniteurs de cellules T humaines à partir de cellules souches / progénitrices hématopoïétiques. Cette stratégie fournit un modèle efficace pour l'étude fondamentale des régulateurs essentiels au cours du développement précoce des cellules T humaines. En outre, il fournit un modèle sûr pour fournir rapidement et abondamment des progéniteurs de cellules T humaines pour des applications cliniquesThymus seeding progenitors migrate into the thymus and initiate T cell differentiation program. The regulation of T cell development is tightly associated with the thymus microenvironment. However, due to the limited model, the mechanism of human T cell development has not been deeply clarified. Thus, we developed an in vitro stroma-free system to support human early T cell development from both neonate and adult human hematopoietic stem / progenitor cells based on Notch ligand DL-4. These T cell progenitors generated in DL-4 system exhibit similar characters as human immature T thymocytes. Moreover, they were proved to have T cell reconstruct potential when transplanted to NOD/SCID/gamma(c)- / - mice, which could differentiate into mature T cell with highly diverse TCR repertoire. Furthermore, we optimized the system by involving TNFa cytokine, which could dramatically enhance the in vitro generation of T-cell progenitors through ameliorating cell survival and proliferation of T-cell precursors, as well as fastening early T lineage differentiation. We demonstrate the regulation of TNFa on T cell progenitors is mainly based on the activation of NFkB signaling, as well as its regulation on inhibitor of apoptosis protein. Overall, this thesis describes a strategy for in vitro generation of human T-cell progenitors from hematopoietic stem/ progenitor cells based on Notch signaling. This strategy provides an effective model for fundamental study to explore essential regulators during human early T cell development. Moreover, it provides a safe model to rapidly supply abundant human T-cell progenitors for clinical applications
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Saiki, Norikazu. „Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenitors“. Kyoto University, 2018. http://hdl.handle.net/2433/232478.
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Pirman, Megan. „An In Vitro Study on the Role of Endothelial Cell Connexin43 Gap Junctions in the Regulation of Hematopoietic Stem and Progenitor Cells Traffic“. University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1267459743.
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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.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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Joshi, Shrinidh Ashokkumar. „Hypoxic Regulation of Angiotensin-Converting Enzyme 2 and Mas Receptor in Hematopoietic Stem/Progenitor Cells: A Translational Study“. Diss., North Dakota State University, 2018. https://hdl.handle.net/10365/28961.
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Vascular disease is the leading cause of mortality and morbidity in the western world, and account for the 1 of every 3 death?s in the US, but a cure for vascular disease is yet to be realized. Hematopoietic stem progenitor cells (HSPCs) are mobilized from bone marrow and have the innate propensity to accelerate vascular repair by reendothelialization and revascularization of ischemic areas. The vasoreparative ability of HSPCs is largely due to their capacity to home to the areas of hypoxia and their sensitivity to hypoxia plays a critical role in the vasoreparative functions of these cells. The discovery of vasoreparative potential of HSPCs resulted in a breakthrough approach of cell-based therapies for the treatment of ischemic vascular diseases. However, success of this approach is essentially dependent on the number of cells that could be collected from an individual. Therefore, novel mechanism-based strategies are needed to enhance the outcomes of autologous cell-based therapies in poor mobilizers and older adults. Recent evidence of a potential role of the vasoprotective axis of the renin angiotensin system (RAS) in HSPCs functions offers a breakthrough. Angiotensin-(1-7), the primary mediator of the protective functions which acts on Mas receptor (MasR), is generated by angiotensin converting enzyme-2 (ACE2). In this study, we tested the effects of hypoxia on stimulation of vasoreparative potential of HSPCs and in upregulation of ACE2 and MasR. Importantly, we delineated the molecular mechanism of hypoxic exposure in regulation of ACE2 and MasR in a HIF1?- dependent manner and hypoxic exposure induced shedding of the membrane bound ACE2 in HSPCs. We used luciferase, a reporter assay, cell-based assays, gene/protein expression studies and pharmacological strategies in human and mouse HSPCs to test our hypotheses. To verify the biological significance of hypoxia, we performed in vivo studies in mice and humans, which recapitulated the in vitro observations on vascular protective axis of RAS in HSPCs. Collectively, these studies provided mechanistic insights into hypoxic regulation of vascular protective axis of RAS in HSPCs and also provided compelling evidence for the clinical use of hypoxia as a promising approach for enhancing the vasoreparative outcomes of cell-based therapies.American Heart Association grant, 13SDG16960025
National Institutes of Health, National institute of Aging (NIA), 1R01AG056881
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Hovey, Owen. „Characterization of Proteins Released by Osteoblasts That Promote Expansion of Hematopoietic Progenitors“. Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38012.
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Umbilical cord blood (UCB) is a source of hematopoietic stem and progenitor cells (HSPC) used for allogeneic transplantation. Ex vivo expansion of HSPC can improve the slow platelet and neutrophil engraftment associated with UCB transplants. HSPCs reside in niches, some of which are near the endosteal bone surface, where they can associate with immature osteoblasts. Interestingly, osteoblasts can enhance the growth of HSPC in culture and their platelet engraftment activity. Using a proteomics approach, I identified 47 differentially expressed proteins between mesenchymal stem cells and immature osteoblasts. Several of these were previously implicated in HSPC maintenance such as IGF2, IGFBP2, DCN, GAS6 and VCAM1. Moreover, several other proteins belong to the alternative and classical complement pathways. Finally, I discovered that microvesicles found in osteoblast conditioned medium may also modulate the growth of HSPC, at least in ex vivo cultures.
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Bauer, Nicola, Ana-Violeta Fonseca, Mareike Florek, Daniel Freund, József Jászai, Martin Bornhäuser, Christine A. Fargeas und Denis Corbeil. „New Insights into the Cell Biology of Hematopoietic Progenitors by Studying Prominin-1 (CD133)“. Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136136.
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Prominin-1 (alias CD133) has received considerable interest because of its expression by several stem and progenitor cells originating from various sources, including the neural and hematopoietic systems. As a cell surface marker, prominin-1 is now used for somatic stem cell isolation. Its expression in cancer stem cells has broadened its clinical value, as it might be useful to outline new prospects for more effective cancer therapies by targeting tumor-initiating cells. Cell biological studies of this molecule have demonstrated that it is specifically concentrated in various membrane structures that protrude from the planar areas of the plasmalemma. Prominin-1 binds to the plasma membrane cholesterol and is associated with a particular membrane microdomain in a cholesterol-dependent manner. Although its physiological function is not yet determined, it is becoming clear that this cell surface protein, as a unique marker of both plasma membrane protrusions and membrane microdomains, might reveal new aspects of the cell biology of rare stem and cancer stem cells. The aim of this review is to outline the recent discoveries regarding the dynamic reorganization of the plasma membrane of rare CD133+ hematopoietic progenitor cells during cell migration and divisionDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Hoppe, Philipp [Verfasser], und Thomas [Akademischer Betreuer] Cremer. „Continuous quantification of transcription factor dynamics in individual hematopoietic stem and progenitor cells / Philipp Hoppe. Betreuer: Thomas Cremer“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1077439377/34.
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Hoppe, Philipp Verfasser], und Thomas [Akademischer Betreuer] [Cremer. „Continuous quantification of transcription factor dynamics in individual hematopoietic stem and progenitor cells / Philipp Hoppe. Betreuer: Thomas Cremer“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-187381.
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An, Ningfei, Bo Cen, Houjian Cai, Jin H. Song, Andrew Kraft und Yubin Kang. „Pim1 kinase regulates c-Kit gene translation“. BIOMED CENTRAL LTD, 2016. http://hdl.handle.net/10150/622957.
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Background: Receptor tyrosine kinase, c-Kit (CD117) plays a pivotal role in the maintenance and expansion of hematopoietic stem/progenitor cells (HSPCs). Additionally, over-expression and/or mutational activation of c-Kit have been implicated in numerous malignant diseases including acute myeloid leukemia. However, the translational regulation of c-Kit expression remains largely unknown. Methods and results: We demonstrated that loss of Pim1 led to specific down-regulation of c-Kit expression in HSPCs of Pim1(-/-)mice and Pim1(-/-)2(-/-)3(-/-) triple knockout (TKO) mice, and resulted in attenuated ERK and STAT3 signaling in response to stimulation with stem cell factor. Transduction of c-Kit restored the defects in colony forming capacity seen in HSPCs from Pim1 (-/-) and TKO mice. Pharmacologic inhibition and genetic modification studies using human megakaryoblastic leukemia cells confirmed the regulation of c-Kit expression by Pim1 kinase: i.e., Pim1-specific shRNA knockdown down-regulated the expression of c-Kit whereas overexpression of Pim1 up-regulated the expression of c-Kit. Mechanistically, inhibition or knockout of Pim1 kinase did not affect the transcription of c-Kit gene. Pim1 kinase enhanced c-Kit S-35 methionine labeling and increased the incorporation of c-Kit mRNAs into the polysomes and monosomes, demonstrating that Pim1 kinase regulates c-Kit expression at the translational level. Conclusions: Our study provides the first evidence that Pim1 regulates c-Kit gene translation and has important implications in hematopoietic stem cell transplantation and cancer treatment.
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McKinnon, Timothy [Verfasser]. „Hematopoietic Stem / Progenitor Cells and placental vascular development : in vitro study on the role of oxygen and stromal-derived factor-1alpha in the establishment of a stem cell niche / Timothy McKinnon“. Gießen : Universitätsbibliothek, 2007. http://d-nb.info/1058561669/34.
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Bauer, Nicola, Ana-Violeta Fonseca, Mareike Florek, Daniel Freund, József Jászai, Martin Bornhäuser, Christine A. Fargeas und Denis Corbeil. „New Insights into the Cell Biology of Hematopoietic Progenitors by Studying Prominin-1 (CD133)“. Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27699.
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Prominin-1 (alias CD133) has received considerable interest because of its expression by several stem and progenitor cells originating from various sources, including the neural and hematopoietic systems. As a cell surface marker, prominin-1 is now used for somatic stem cell isolation. Its expression in cancer stem cells has broadened its clinical value, as it might be useful to outline new prospects for more effective cancer therapies by targeting tumor-initiating cells. Cell biological studies of this molecule have demonstrated that it is specifically concentrated in various membrane structures that protrude from the planar areas of the plasmalemma. Prominin-1 binds to the plasma membrane cholesterol and is associated with a particular membrane microdomain in a cholesterol-dependent manner. Although its physiological function is not yet determined, it is becoming clear that this cell surface protein, as a unique marker of both plasma membrane protrusions and membrane microdomains, might reveal new aspects of the cell biology of rare stem and cancer stem cells. The aim of this review is to outline the recent discoveries regarding the dynamic reorganization of the plasma membrane of rare CD133+ hematopoietic progenitor cells during cell migration and division.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Costa, Everton de Brito Oliveira. „Caracterização das Células-Tronco/Progenitoras Hematopoéticas obtidas de Células-Tronco Embrionárias Humanas In Vitro em Sistema de Co-Cultivo com Fibroblastos de Embriões Murinos“. Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-14062012-131047/.
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A hematopoese tem sido bem descrita em modelos murinos nas últimas décadas, contudo, trabalhos demonstrando os mecanismos da hematopoese em humanos ainda são escassos. A derivação da primeira linhagem de células-tronco embrionárias humanas (CTEhs) em 1998, gerou novas perspectivas tanto para o estudo da hematopoese na tentativa de mimetizar o que ocorre naturalmente durante o desenvolvimento embrionário, quanto para a aplicação clínica das células hematopoéticas obtidas a partir da diferenciação dessas células. Contudo, apesar de inúmeros trabalhos terem demonstradoa obtenção de células hematopoéticas a partir de CTEhs, os protocolos têm gerado quantidades variáveis de células, com baixa eficiência e com propriedades funcionais de células primitivas. Desse modo, este trabalho procurou estabelecer um modelo próprio de diferenciação de CTEhs-H1 em células progenitoras hematopoéticas para que estas pudessem ser melhor caracterizadas e obtidas de forma mais eficiente. Para isto, foi desenvolvido um sistema de diferenciação baseado no co-cultivo da linhagem de CTEh-H1 com fibroblastos de embrião de camundongo (MEFs), em meio de diferenciação suplementado soro fetal bovino (SFB) e citocinas e fatores de crescimento hematopoéticos em baixas concentrações. Como resultado, o desenvolvimento do presente trabalho permitiu o estabelecimento de um método para geração de populações mistas de células enriquecidas em CPHs positivas para o marcador CD45, o qual mostrou ser coexpresso com outros marcadores hematopoéticos (CD31, CD43, CD71 e CD38), e células hematopoéticas maduras positivas para marcadores mielóide-específicos (235a, CD14, CD15, CD16) e com características morfológicas típicas. Foi demonstrado que as células obtidas expressavam genes relativos ao sistema hematopoético (CD45, CD31, runx1, tal1, lmo2, prom1, CD34 e notch1), e possuíam potencial clonogênico in vitro da ordem de 1/574 células plaqueadas. Em adição, corroboramos os achados de que as células hematopoéticas apresentam duas origens distintas: a partir do endotelio hemogênico e a partir de células com propriedades hemangioblásticas independentes do endotélio hemogênico.Hematopoiesis has been well described in murine models in recent decades, however, studies demonstrating the mechanisms of hematopoiesis in humans are still scarce. The first human embryonic stem cells line (hESCs) derived in 1998, has generated new perspectives about the study of hematopoiesis as in attempting to mimic what naturally occurs during embryonic development, as for clinical application of hematopoietic cells obtained from the differentiation of these cells. However, although numerous studies have shown the production of hematopoietic cells derived from hESCs, the protocols have generated varying quantities of cells with low efficiency and functional properties of primitive stem cells. Thus, this study sought to establish our own model for hESC-H1 differentiation in hematopoietic progenitor cells so that they could be better characterized and obtained more efficiently. For this way, we developed a differentiation system based on co-culture of hESC-H1 line with inactivated mouse embryonic fibroblasts (MEFs) in differentiation medium supplemented with fetal calf serum (FCS) and cytokines and hematopoietic growth factors in low concentrations. As a result, the development of this study allowed the establishment of a method for generation of mixed population of cells enriched in hematopoietic progenitor cells positive for the marker CD45, which proved to be co-expressed with other hematopoietic markers (CD31, CD43, CD71 and CD38), and mature hematopoietic cells positive for myeloid-specific markers (235a, CD14, CD15, CD16) and morphological characteristics typical. It was shown that these cells expressed genes related to the hematopoietic system (CD45, CD31, runx1, TAL1, LMO2, prom1, CD34 and NOTCH1), and had clonogenic potential in vitro of 1/574 plated cells. In addition, we corroborate the findings that hematopoietic cells have two distinct origins: they can arise as from an hemogenic endothelium as from cells with hemangioblastic properties by an hemogenic endothelium-independent way.
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Esplin, Brandt L. „Replenishment of innate immune system in health and disease“. Oklahoma City : [s.n.], 2009.
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Zeng, Hui. „Requirement of the transcription factor and onco-protein Gfil for the development and function of hematopoietic stem cells and progenitor cells“. [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972510176.
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Buchanan, Sandhya S. „Preservation of two therapeutic biopharmaceuticals using sugars and polymers : hematopoietic stem and progenitor cells and a live attenuated viral vaccine /“. Connect to full text via ProQuest. IP filtered, 2006.
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Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado, 2006.Typescript. Includes bibliographical references (leaves 191-216). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Chisi, John Eugenes. „The regulatory role of AcSDKP and angiotensin 1-converting enzyme (ACE) inhibitors on haematopoietic stem and progenitor cell proliferation“. Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/14971.
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Negative regulatory factors inhibit the proliferation of haematopoietic stem cells thus protecting them from differentiation pressures. One of the negative regulators of stem cell proliferation is the tetrapeptide Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP). This peptide is endogenously produced in vivo and long term bone marrow cultures and is degraded by angiotensin 1-converting enzyme (ACE) both in vivo and in vitro. The aim of these investigations was to study the role of ACE on haematopoietic stem and progenitor cell proliferation. Since the N-domain ACE active has been implicated in AcSDKP degradation, an analysis of two ACE inhibitors (captopril and lisinopril) shown to have differential effects on the N-domain ACE active site was conducted. Both captopril and lisinopril equally reduced ACE activity in plasma in vitro. However, captopril had a lesser effect on reducing serum ACE activity in vitro than lisinopril. Captopril and AcSDKP together reduced the proportion of GM-CFC in S-phase after 7 hours of in vitro incubation. In addition, ACE resistant AcSDKP analogue (AcSDPψKP) when incubated with bone marrow cells in the absence of captopril also reduced the proportion of GM-CFC in S-phase. This finding suggest that the effect of captopril and AcSDKP on GM-CFC proliferation was due to AcSDKP alone. Haematopoietic stem cells were induced into cell cycle by in vivo administration of either 2 Gy-γ-irradiation or the two cytotoxic drugs, cytosine arabinoside (Ara-C) (100 mg/kg i.p.) or 5 flourouracil (5 FU) (150 mg/kg i.v). Bone marrow cells were sampled and incubated in vitro for up to 24 hours. Captopril together with AcSDKP reduced the proportion of high proliferative colony forming cells-1 (HPP-CFC-1) in S-phase following 2 Gy-γ-irradiation. Lisinopril together with AcSDKP had no such effect. In addition, captopril alone in vitro reduced the proportion of HPP-CFC-1 in S-phase induced into cell cycle by cytotoxic drugs. Lisinopril had no such effect. Incubation alone reduced the proportion of HPP-CFC-1 in S-phase in cytotoxic drug treated bone marrow cells. When cultures, which were incubated with captopril, were assayed for AcSDKP levels, captopril induced an increase in AcSDKP levels in both control normal bone marrow cells and cells derived from Ara-C treated mice. However, it did not affect AcSDKP levels in cultures derived from 5 FU and 2 Gy treated mice, AcSDKP together with captopril were shown to inhibit S-phase cell entry of HPP-CFC-1 when they were incubated with bone marrow cells derived from mice treated with either 2 Gy-γ-irradiation or cytotoxic drug insults. Interestingly, captopril was unable to reduce the proportion of SA2 leukaemic cells in S-phase Captopril on its own at therapeutic doses reduced the proportion of HPP-CFC- 1 in S-phase in vivo regardless of the insult used to induce HPP-CFC-1 into cell cycle. Lisinopril slightly reduced the proportion of HPP-CFC-1 in S-phase following Ai-a-C treatment only. Captopril induced an in vivo increase in AcSDKP levels in all the models tested. Captopril also reduced the proportion of HPP-CFC-1 and GM-CFC in S-phase following fractionated doses of Ara-C. Captopril's inhibitory effect on GM- CFC proliferation following fractionated dose of Ara-C was diminished after 7 days while it was sustained with HPP-CFC-1. Long-term bone marrow cultures revealed that captopril and AcSDxj/KP had the same effect on cellularities of both layers and on the proliferation of HPP-CFC and GM-CFC in both layers. From the present investigations, it can be concluded that captopril is a potent inhibitor of HPP-CFC-1 proliferation. This effect may in part be mediated by AcSDKP mechanism.
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Alsheikh, Manal. „Impact of the Maturation Status of Osteoblasts on Their Hematopoietic Regulatory Activity“. Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35899.
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Osteoblasts (OST) provide strong intrinsic growth modulatory activities on hematopoietic stem and progenitor cells via different mechanisms that include secretion of growth factors, and cellular interaction. Previously we showed that medium conditioned by mesenchymal stromal cell (MSC)-derived osteoblasts (M-OST) improve the expansion of cord blood (CB) CD34+ cells. I hypothesize that the hematopoietic supporting activity of M-OST would vary as a function of their maturation. This was tested by producing osteoblast conditioned media (OCM) from M-OST at distinct stages of maturation, and testing their growth regulatory activities in CB CD34+ cell cultures. My results showed that some of the growth promoting activity of OCM on CB cells are not dependent on the maturation status, while others are and those are largely independent of Notch signalling. In conclusion, these results provide further evidence that osteoblasts release factors that can promote the growth of immature CB progenitors in a Notch-independent way.
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Bissels, Ute [Verfasser]. „Combined analysis of microRNA and mRNA signatures in human hematopoietic stem and progenitor cells using a novel microarray quantification system / Ute Bissels“. Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/1016243669/34.
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Almoflehi, Sakhar. „Cord Blood CD34+ Expansion Using Vitamin-C: An Epigenetic Regulator“. Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41413.
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Vitamin-C (Vit-C) has been shown to modulate hematopoietic stem cells and leukemia stem cell frequency in-vivo. Herein, Vit-C analogue, L-ascorbic acid 2-phosphate (AA2P), was investigated as a new potential HSC expansion agonist. Cord blood CD34+ cells were expanded in cultures with or without AA2P. AA2P induced a 2-fold increase in the expansion of stem and progenitor subsets including lymphoid-primed multi-potential progenitors (p<0.05, n=3) and functional colony forming progenitors. The functional properties of AA2P grafts was evaluated with a xenotransplant model. Superior platelet levels in the periphery (p<0.05) and human bone marrow engraftment (median 75% hCD45+ cells for AA2P Vs. 48% for PBS control at week-22, n=3, p<0.05) was detected in AA2P cohorts Vs. control. In summary, my results demonstrate that AA2P is a new stem and progenitor expansion agonist with AA2P-expanded stem and progenitor cells capable of increased engraftment and higher platelet recovery. These findings may aid to overcome cord blood limitations; thereby, improving clinical relevance.
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Pessolato, Alícia Greyce Turatti. „Caracterização das células-tronco do saco vitelino e análise ultraestrutural da membrana vitelina de embriões ovinos (Ovis aries)“. Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-07082012-183204/.
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O saco vitelino é o único anexo embrionário presente em todas as espécies dos embriões vertebrados, répteis, aves e mamíferos. Em mamíferos domésticos o saco vitelino é inicialmente grande, pois nestas espécies ele é transitório. Após a implantação, surge no mesênquima lateral à notocorda agrupamentos de células, denominados ilhotas sanguíneas, que representam os progenitores dos sistemas vascular e hematopoético: os hemangioblastos. Os hemangioblastos centrais das ilhas sanguíneas formam as primeiras células-tronco hematopoéticas, enquanto os hemangioblastos periféricos se diferenciam em angioblastos, os precursores dos vasos sanguíneos. O desenvolvimento inicial da atividade hematopoética no saco vitelino conduz a hipótese de que esse tecido é o local primário de desenvolvimento hematopoético e que as células-tronco derivadas dele semeiam os outros sítios intraembriônicos. Foi possível observar nas análises microscópicas que realmente existe uma relação entre ambas linhagens. Nas análises de expressão gênica, alguns genes expressos pelo hemangioblasto apresentaram alta expressão nas análises D+0 e outros genes também específicos do hemangioblasto, porém em estágios secundários de diferenciação como os encontrados na região aórtica, a nível de endotélio hemogênico apresentaram altos níveis de expressão após 3 dias em cultivo. Concluímos portanto, que o saco vitelino por ser o local primário de formação das células sanguíneas e endoteliais nos estágios iniciais da embriogênese, por serem primitivas e, portanto não expressarem marcadores de células maduras na sua superfície, tornam estas células uma importante fonte de células-tronco relevante para a Terapia Celular para hemofilia e muitas outras doenças humanas.The yolk sac is the single attachment embryo present in all species of vertebrate embryos, reptiles, birds and mammals. In domestic mammals the yolk sac is initially large, since these species it is transient. After implantation, appears in the lateral mesenchyme to the notochord cell clusters, called \"blood islands\" that represent the progenitors of vascular and hematopoietic systems: the hemangioblasts. The central islands hemangioblasts form the first blood hematopoietic stem cells, while peripheral hemangioblasts, the angioblastic differentiate into the precursors of blood vessels. The initial development of the yolk sac hematopoietic activity leads to the hypothesis that this tissue is the primary site of development and that hematopoietic stem cells derived from them sow other intraembryos sites. It was observed in the microscopic analysis that there is indeed a relationship between the two lineages. In the analysis of gene expression, some genes expressed by hemangioblasts showed high expression in D+0 and other specific genes also hemangioblasts, but in secondary stages of differentiation as found in the aortic region, the level of hemogenic endothelium showed high levels of expression after 3 days in culture. We therefore conclude that the yolk sac to be the primary site of formation of blood and endothelial cells in the early stages of embryogenesis, for its cells be primitive and therefore do not express markers of mature cells on the surface, these cells become an important source of cells relevant to stem cell therapy for hemophilia and many other human diseases.
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Varagnolo, Linda [Verfasser], und Albrecht Manfred [Gutachter] Müller. „PRC2 inhibition counteracts the culture-associated loss of engraftment potential of human cord blood-derived hematopoietic stem/progenitor cells / Linda Varagnolo. Gutachter: Albrecht Manfred Müller“. Würzburg : Universität Würzburg, 2015. http://d-nb.info/1111560021/34.
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Burk, Alexandra Serena [Verfasser], und Motomu [Akademischer Betreuer] Tanaka. „Quantifying Adhesion and Morphological Dynamics of Human Hematopoietic Stem and Progenitor Cells on Novel In Vitro Models of Bone Marrow Niche / Alexandra Serena Burk ; Betreuer: Motomu Tanaka“. Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/118050254X/34.
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Osma, Córdoba María del Mar. „Estudio de los progenitores hematopoyéticos en el trasplante autogénico en pacientes con carcinoma de mama. Study of the hematopoietic progenitors in patients with breast cancer undergoing autologous peripheral blood stem cell transplantation“. Doctoral thesis, Universidad de Murcia, 2000. http://hdl.handle.net/10803/96058.
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En el marco del trasplante autólogo de progenitores de sangre periférica (TASPE), cincuenta pacientes diagnosticadas de cáncer de mama fueron incluidas en un estudio prospectivo en el que se evaluaba el contenido basal de progenitores CD34+/ CD71- en médula ósea (M.O.), como parámetro predictivo de la movilización de células CD34 tras G-CSF. Además, se estudió el papel del G-CSF, tanto a corto plazo como en la regeneración de progenitores medulares al año del procedimiento. El G-CSF post-TASPE demostró acelerar la recuperación de neutrófilos, pero no hubo diferencias significativas en la recuperación plaquetaria, soporte transfusional, días de fiebre, administración de antibióticos o de estancia hospitalaria. Respecto a los precursores hematopoyéticos en M.O. un año después del TASPE, se encontraron concentraciones más bajas del total de células CD34+, tanto comprometidas (CD34+/CD33+), como inmaduras (CD34+/CD71-) en pacientes tratadas con G-CSF al
compararlas con aquellas que no recibieron la citoquina. La administración de G-CSF post-TASPE no parece afectar significativamente el resultado del procedimiento, pero podría comprometer la hematopoyesis medular a largo plazo.In the setting of autologous peripheral blood stem cell transplantation (APBSCT), fifty patients diagnosed with breast cancer were included in a prospective study evaluating the bone marrow (BM) CD34+/CD71- cell content, as a predictive parameter of the CD34 cell mobilization after rhG-CSF. We also analyzed data to compare post APBSCT rhG-CSF administration in terms of the short-term benefit and myeloid marrow regeneration after 1 year. Post-APBSCT rhG-CSF was shown to accelerate neutrophil recovery, but there were no significant differences in platelet recovery, transfusion requirements, days of fever, antibiotic administration or inhospital stay. With regard to BM hematopoietic precursors 1 year after APBSCT, significantly lower concentrations of total CD34+ cells, committed CD34+/CD33+ subsets, and more immature CD34+/CD71- cells, were found in patients treated with rhG-CSF compared with patients not having received the cytokine. Post-APBSCT rhG-CSF administration does not appear to beneficially affect procedure outcome, but might even impair long-term marrow hematopoiesis.
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Paleske, Lisa von [Verfasser], und Andreas [Akademischer Betreuer] Trumpp. „Identification of a novel enhancer region 1.7 Mb downstream of the c-myc gene controlling its expression in hematopoietic stem and progenitor cells / Lisa von Paleske ; Betreuer: Andreas Trumpp“. Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180735145/34.
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Forte, Andresa. „Expansão ex vivo das células-tronco hematopoiéticas do sangue do cordão umbilical: análise comparativa da proliferação celular em cocultura de células-troco mesenquimais provenientes do endotélio vascular do cordão umbilical e do tecido adiposo“. Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5167/tde-25022015-085731/.
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INTRODUÇÃO: As células-tronco hematopoiéticas (CTH) do sangue do cordão umbilical (SCU) têm sido utilizadas com sucesso para o tratamento de doenças malignas e não malignas. No entanto, algumas unidades de SCU podem apresentar baixa quantidade de células nucleadas totais (CNT). Algumas abordagens têm sido sugeridas para evitar problemas em relação à baixa concentração de CTH no transplante, como a administração de duas unidades de SCU para o paciente e a expansão ex vivo de CTH. OBJETIVO: Avaliar as taxas de proliferação celular na expansão ex vivo do SCU em sistema de cocultura com células-tronco mesenquimais (CTM) obtidos a partir de diferentes fontes com alta e baixa confluência e adicionando-se ou não coquetel de citocinas no meio de cultura. MÉTODOS: Este estudo foi aprovado pelo Comitê de Ética de Pesquisa (CAPPesq) do Hospital das Clínicas da Faculdade de Medicina da USP. A coleta do SCU (n =10) foi realizada após o nascimento do bebê e expulsão da placenta. O processamento foi realizado utilizando o método de redução de volume, o qual consiste em depleção de eritrócitos. As amostras de CTM provenientes do endotélio vascular do cordão umbilical foram obtidas de doadores diferentes (n=3) e o tecido adiposo (n=3) do inventário do LIM-31. A expansão das CNT e das células com expressão de marcadores CD133+/CD34+ foram observados depois de sete dias de cultura. Além disso, o ensaio para análise de unidades de formadoras de colônias (UFC) foi realizado em todas as amostras antes e depois da expansão do SCU. Para a expansão em sistema de cocultura foi separado dois grupos para ambas as fontes de CTM (Grupo I - cocultura com adição de coquetel de citocinas vs. Grupo II - cocultura sem citocinas). RESULTADOS: Após sete dias, no grupo I com cocultura confluente, a taxa de proliferação de CNT foi duas vezes maior ao comparar com cocultura subconfluente (35 vs. 16 vezes). No mesmo grupo também foi possível evidenciar elevada taxa de proliferação de células CD133+/CD34+. O índice de proliferação das UFC no grupo I aumentou até oito vezes. A cocultura subconfluente tanto do endotélio vascular do cordão umbilical como do tecido adiposo apresentou menor rendimento em comparação as CTM confluentes. A expansão das células na presença de citocinas apresentou maior proliferação celular ao comparar às coculturas sem adição de citocinas. CONCLUSÃO: Este estudo mostrou que para alto rendimento de células do SCU, o sistema de cocultura requer adição de coquetel de citocinas e CTM confluente independentemente da fonte utilizadaINTRODUCTION: Umbilical cord blood (UCB) hematopoietic stem cells have been successfully used for the treatment of both malignant and non-malignant diseases. Nevertheless, some UCB units could have low total nucleated cells (TNC) dose. Several approaches have been suggested to avoid inadequacy problems of hematopoietic stem cells (HSC) number for transplantation, such as administration of two UCB units to the patient and HSC ex vivo expansion. OBJECTIVE: Evaluate UCB ex vivo expansion proliferative rates in a high and low mesenchymal stem cells (MSC) confluence feeder layer obtained from different MSC sources and by adding or not cytokines cocktail into the medium. METHODS: This study was approved by the Research Ethic Committee (CAPPESQ) of Hospital das Clínicas da Faculdade de Medicina da USP. The collection of UCB (n=10) was made after delivery of the infant and the expulsion of placenta. Processing was performed using volume reduction method which consists in red blood depletion. MSC samples from umbilical cord endothelium were obtained from three different donors and adipose tissue (n=3) obtained from LIM31\'s pattern inventory. The total nucleated cell (TNC), expression of hematopoietic surface markers such as CD133+/CD34+ were observed after seven days of culture. Beyond that, colony forming unit assay (CFU) was performed before and after UCB expansion. The expansion by coculture method was observed in two groups (Group I - coculture with cytokines cocktail added vs. Group II- coculture without cytokines cocktail) for both MSCs sources. RESULTS: After seven days, analysis of confluent coculture showed that TNC proliferation rate ware almost 2 times higher than in subconfluent coculture (35 vs. 16-fold) in Group I and also revealed higher proliferative rate in CD133+/CD34+ cells considering. CFU showed similar increase after seven days of culture in comparison of day 0 (up to 8-fold). Subconfluent coculture for both umbilical cord endothelium and adipose tissue showed lower yield compared with those with high MSC confluence. The expansion in the presence of cytokines showed higher cell proliferation compared to the cocultures without addition of cytokines. CONCLUSION: This study showed that coculture system may require the addition of cytokines cocktail in the media and confluent MSC regardless of source for high yield of UCB cells