The production of fully functional haematopoietic stem cells (HSCs) for clinical transplantation is a highly sought after goal in the field of regenerative medicine. Given their capacity for extensive self-renewal and differentiation into any cell type, human pluripotent stem cells (hPSCs) provide a potentially limitless source of haematopoietic cells in vitro for clinical application. However, to date, fully functional HSCs have not been produced from hPSCs without the overexpression of transcription factors. In this study I first investigated the production of HSCs and haematopoietic progenitor cells (HPCs) in an established clinical-grade haematopoietic differentiation protocol. I demonstrated the efficient and reproducible production of HPCs but showed that the strategy did not produce fully functional HSCs that could repopulate the haematopoietic system of immune-deficient mice. Modification of the protocol by manipulation of the hedgehog signalling pathway and co-aggregation with OP9 stromal cells did not provide any significant enhancement of HPC production. To gain the required knowledge with which to improve our current protocol, I therefore switched my focus towards studying the development of HSCs in the early human embryo. It has been shown that HSCs first emerge from the ventral wall of the dorsal aorta in the aorta-gonad-mesonephros (AGM) region of the human embryo but the precise location and the mechanisms underpinning this process remain unknown. In this study, I established a culture system to map the spatio-temporal distribution of HSCs and to investigate the presence of HSC precursors. I showed that embryonic HSCs emerge predominantly around and above the vitelline artery entry point in the dorsal aorta and can be maintained in our explant culture system. I then performed RNA-sequencing of cells derived from AGM sub-regions, and this identified molecular signatures which could potentially underlie the ventral polarity of HSC emergence in the AGM. To elucidate the role of the stromal compartment in this unique haematopoietic niche, I derived stromal cell lines from the human AGM region and showed they were capable of supporting haematopoiesis in vitro. This work has provided some important insights into the mechanisms regulating HSC development in the human AGM region and identified interesting candidate molecules for future testing in differentiation protocols. This knowledge brings us a step closer to the successful in vitro production of HSCs for clinical use.

This thesis consists in six articles and a comprehensive summary. • The pourpose of the summary is to introduce the AGM theory of belief change and to exemplify the diversity and significance of the research that has been inspired by the AGM article in the last 25 years. The research areas associated with AGM was divided in three parts: criticisms, where we discussed some of the more common criticisms of AGM. Extensions where the most common extensions and variations of AGM are presented and applications where we provided an overview of applications and connections with other areas of research. • Article I elaborates on the connection between partial meet contractions [AGM85] and kernel contractions [Han94a] in belief change theory. Also both functions are equivalent in belief sets, there are notequivalent in belief bases. A way to define incision functions (used in kernel contractions) from selection functions (used in partial meet contractions) and vice versa is presented. It is explained under which conditions there are exact correspondences between selection and incision functions so that the same contraction operations can be obtained by using either of them. • Article II proposes an axiomatic characterization for ensconcement-based contraction functions, belief base functions proposed byWilliams and relates this function with other kinds of base contraction functions. • Article III adapts the Fermé and Hansson model of Shielded Contraction [FH01] as well as Hansson et all Credibility-Limited Revision [HFCF01] for belief bases, to join two of the many variations of the AGM model [AGM85], i.e. those in which knowledge is represented through belief bases instead of logic theories, and those in which the object of the epistemic change does not get the priority over the existing information as it is the case in the AGM model. • Article IV introduces revision by comparison a refined method for changing beliefs by specifying constraints on the relative plausibility of propositions. Like the earlier belief revision models, the method proposed is a qualitative one, in the sense that no numbers are needed in order to specify the posterior plausibility of the new information. The method uses reference beliefs in order to determine the degree of entrenchment of the newly accepted piece of information. Two kinds of semantics for this idea are proposed and a logical characterization of the new model is given. • Article V focuses on the extension of AGM that allows change for a belief base by a set of sentences instead of a single sentence. In [FH94], Fuhrmann and Hansson presented an axiomatic for Multiple Contraction and a construction based on the AGM Partial Meet Contraction. This essay proposes for their model another way to construct functions: Multiple Kernel Contraction, that is a modification of Kernel Contraction,proposed by Hansson [Han94a] to construct classical AGM contractions and belief base contractions. • Article VI relates AGM model with the DFT model proposed by Carlos Alchourrón [Alc93]. Alchourrón devoted his last years to the analysis of the notion of defeasible conditionalization. His definition of the defeasible conditional is given in terms of strict implication operator and a modal operator f which is interpreted as a revision function at the language level. This essay points out that this underlying revision function is more general than AGM revision. In addition, a complete characterization of that more general kind of revision that permits to unify models of revision given by other authors is given. / QC 20110211

Das Humane Immundefizienzvirus (HIV) ist der Erreger von AIDS und als Zoonose von den Schimpansen (HIV-1) bzw. den Rauchmangaben (HIV-2) auf die menschliche Population übergesprungen. Diese Primatenspezies sind die natürlichen Wirte für die simianen verwand-ten Viren SIVcpz bzw. SIVsm. Die nicht-natürlichen Virus-Wirt-Beziehungen der Immundefizienzviren resultieren in einem pathogenen Verlauf, wie HIV im Menschen und SIVmac in Rhesusmakaken. Die natürlichen Wirte Rauchmangaben, Schimpansen, Afrikanische Grüne Meerkatzen (AGM) und viele mehr entwickeln hingegen kein simianes AIDS. Dies erfolgt trotz lebenslanger Infektion mit SIV und einer zur HIV-Infektion im Menschen äquivalenten Viruslast. Die natürlichen Wirte weisen darüber hinaus keine Immunantwort gegen das virale Kernprotein Gag (gruppen-spezifisches Antigen) auf, was ein früh und zahlreich gebildetes Protein während der Virusreplikation ist. Die fehlende humorale Immunantwort könnte die natürlichen Wirte vor Aktivierung des Immunsystems und dadurch auch vor sAIDS bewahren. Frühere Versuche in AGM mit injiziertem SIVagmGag-Protein zeigten zwar, dass die Induktion einer humoralen Immunantwort gegen SIVagmGag möglich ist, diese aber schon nach kurzer Zeit wieder absinkt. Des Weiteren bildete sich durch Infektion mit SIVagm in den Tieren keine anamnestische Immunantwort heraus, die für die Erkennung von gleichen Epitopen maßgeblich ist. Es scheint ein Unterschied in der Erkennung von exogenem injiziertem SIVagmGag-Protein zu endogenem, durch das Virus selbst gebildetem, Protein in den AGM zu bestehen. Folglich wurde die Hypothese aufgestellt, dass eine Immunisierung mit SIVagmGag-DNA unter Umgehung des Unterschieds in der Proteinprozessierung eine anamnestische Immunantwort in den AGM induziert. Um diese Hypothese zu testen und die Gag-Immunreaktion in Abwesenheit anderer viraler Gene bezüglich der Pathogenität zu evaluieren, wurden codonoptimierte SIVagmGag- und SIVmacGag-DNA Immunisierungsvektoren generiert. Die Proteinexpression wurde in vitro und die Immunogenität in Balb/c und C57Bl/6 Mäusen getestet. Jeweils eine Gruppe von vier AGM erhielt bioballistisch SIVagmGag-DNA bzw. SIVmacGag-DNA. Als Kontrollen dienten mit codonoptimierter DNA immunisierte Rhesusmakaken sowie mit Leervektor immunisierte Primaten beider Spezies. Als Kostimulanz wurde zusätzlich jeweils speziesspezifische gmcsf DNA verwendet. Im Gegensatz zu den Rhesusmakaken konnte in den AGM durch DNA-Immunisierung keine zelluläre und nur eine schwache, transiente humorale anamnestische Immunantwort nach Infektion induziert werden, obwohl beide Gag-Proteine endogen produziert wurden. Daher kann die fehlende anamnestische Immunantwort der AGM nach Immunisierung mit Gag-Protein vermutlich nicht auf Unterschiede in der Proteinprozessierung und -erkennung (endogen versus exogen) zurückgeführt werden. Die Ergebnisse dieser Studie deuten an, dass während der Infektion dieses natürlichen Wirtes eine aktive Unterdrückung der anti-Gag-Antikörperantwort stattfindet, möglicherweise induziert durch eine Anergie in Gag-spezifischen T-Helferzellen. / The causative agents of AIDS, the human immunodeficiency viruses (HIV-1 and HIV-2), were transmitted zoonotically to the human population from the natural hosts of the related simian immunodeficiency viruses SIVcpz (chimpanzees) and SIVsm (sooty mangabeys), respectively. In contrast to the outcome of infections in non-natural hosts (e.g. HIV in humans, SIVmac in rhesus macaques), the natural hosts of SIV do not develop simian AIDS-like symptoms despite life-long infection with virus loads matching those seen in HIV-infected humans. Many such natural host primates infected with SIV, such as SIVagm-infected African green monkeys (AGMs), fail to mount an antibody response to the intact viral core protein Gag (group-specific antigen), a protein produced extensively during infection. It has been postulated that this lack of an immune response to Gag could protect the natural hosts from immunopathological effects and therefore from simian AIDS. Previous studies in AGMs indicated that Gag protein produced endogenously during infection is ''seen'' by the immune system differently than that introduced exogenously by protein immunisation, possibly through differences in processing or through specific tolerance at the T-cell level. To address these possibilities, primate studies were performed in which the responses in the natural and non-natural hosts to endogenously produced Gag protein in the absence of other viral genes were compared and the influence of such endogenous priming on the immune response to infection was evaluated. This was achieved by bioballistic immunisation of AGMs and rhesus macaques with codon-optimised DNA coding for SIVagm or SIVmac Gag protein delivered together with DNA coding for the species-specific GM-CSF cytokine. Prior to the primate studies, the DNA constructs were evaluated in BALB/c and C57Bl/6 mice for immunogenicity and protein expression. In contrast to the rhesus macaques, SIVagmGag DNA immunisation of African green mon-keys generally failed to prime for an anamnestic cellular immune response and primed for only a weak, transient anamnestic humoral response to the protein upon infection, despite the proteins resulting from both immunisation and infection being produced endogenously. Differences in protein processing and recognition (endogenous versus exogenous) do not therefore appear to account for the lack of priming for an anamnestic immune response seen using a protein immunogen. Rather, the results seem to indicate that an active suppression of the anti-Gag immune response may occur during infection of this natural host of SIV, possibly by the induction of anergy in Gag-specific Th cells.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Acredita-se que os primeiros progenitores da hematopoese definitiva surjam da diferenciação do endotélio da aorta dorsal, na altura da região da Aorta-Gônada-Mesonefros (AGM). Com o intuito de estudar esta região e o fenótipo das células do endotélio da aorta dorsal nesta posição topográfica, ovos galados de Gallus gallus domesticus L. foram incubados em chocadeira, classificados em estádios de E16 a E25 e processados histotecnologicamente para obtenção de secções seriadas na altura da região AGM. Estas passaram por coloração por Hematoxilina-Eosina, histoquímica para PAS, PAS-diastase e Alcian Blue pH 1.0 e pH 2.5, histoquímica por lectinas fluoresceinadas e imunofluorescência para moléculas de superfície, citoesqueleto e matriz extracelular. Foi observada hipertrofia endotelial no assoalho da aorta nos estádios observados, o qual se apresentava positivo ao PAS, com ocorrência frequente de vacuolizações basais PAS negativas, e o surgimento ocasional de grupamentos celulares intravasculares. Nestes, as células que se destacavam da membrana basal do endotélio expressavam progressivamente mais material PAS positivo, o qual, no entanto, em nenhum momento pareceu se tratar de glicogênio. Em relação às glicosaminoglicanas, notamos a presença predominante de ácido hialurônico por todo o mesênquima da região e em outras estruturas como periferia da notocorda, tubo neural e mesoderma lateral. Ocorreu co-expressão de fibronectina e α-actina de músculo liso em células circunjacentes à aorta, na face ventral do vaso. GFAP e BMP-4 são expressas entre as células do tubo neural e em sua periferia, assim como na notocorda do embrião. As lectinas Abrus precatorius, Lens culinarise Ricinus communis mostraram-se positivas principalmente na região subedotelial do assoalho da aorta nos estádios observados neste trabalho. Bandeiraea simplicifolia exibiu pouca marcação na aorta dorsal e a Arachis hypogeae foi negativa. Outras estruturas da região AGM também expressaram resíduos de açúcares revelados por estas lectinas, tais como: notocorda, tubo neural, mesênquima, intestino primitivo e saco vitelínico. Estes resultados acrescentam elementos morfológicos e bioquímicos ao conhecimento sobre a região AGM de embriões de galinha e sobre o endotélio, possivelmente hemogênico, da aorta dorsal. / Nowadays it is known that firsts definitive hematopoietic progenitors arise from endothelium differentiation of dorsal aorta, at Aorta-Gonad-Mesonephros (AGM) site. In order to study those events and cells phenotype of dorsal aorta endothelium in this topographical site, fertilized eggs of Gallus gallus domesticus L. were incubated, from E16 to E25 and to be processed by histotechonology to obtain serial sections of the AGM site. After this, they were stained with Hematoxilin-Eosin, histochemistry to PAS, diastase PAS and Alcian Blue pH 1.0 and pH 2.5, to obtain a better overview and characterization from cells, also, histochemistry to fluorescein lectins and immunofluorescense to surface molecules, cytoeskeleton andextracellular matrix were performed. Our results showed endothelial hypertrophy of the aorta floor in the stages analyzed, which shown positive for PAS, with frequent appearance of PAS negatives basal vacuolizations and an occasional intravascular cell clusters arise of. It was also observed that cells which were separated from endothelium basal membrane shown progressively were more PAS positive which however in any time seems to be glycogen. Regard of glycosaminoglycans we noted the main presence of hialuronic acid for all the mesenchymes site and in others structures like notochord periphery, neural tube and lateral mesoderm. It was observed fibronectin and smooth muscle α-actin co-expression on aorta surrounding walls, at vessels ventral face. GFAP and BMP-4 are express between the cells of neural tube and surrounding it, as well as at embryo notochord. The lectins Abrus precatorius, Lens culinaris and Ricinus communis showed mostly positive expression on the sub endothelium site of the dorsal aorta floor at the stages analyzed in this work. Bandeiraea simplicifolia showed low expression on dorsal aorta and in Arachis hypogeae it was negative. Other structures of AGMs site also expressed sugar residues revealed by these lectins like: notochord, neural tube, mesenchyme, primitive gut and yolk sac.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Acredita-se que os primeiros progenitores da hematopoese definitiva surjam da diferenciação do endotélio da aorta dorsal, na altura da região da Aorta-Gônada-Mesonefros (AGM). Com o intuito de estudar esta região e o fenótipo das células do endotélio da aorta dorsal nesta posição topográfica, ovos galados de Gallus gallus domesticus L. foram incubados em chocadeira, classificados em estádios de E16 a E25 e processados histotecnologicamente para obtenção de secções seriadas na altura da região AGM. Estas passaram por coloração por Hematoxilina-Eosina, histoquímica para PAS, PAS-diastase e Alcian Blue pH 1.0 e pH 2.5, histoquímica por lectinas fluoresceinadas e imunofluorescência para moléculas de superfície, citoesqueleto e matriz extracelular. Foi observada hipertrofia endotelial no assoalho da aorta nos estádios observados, o qual se apresentava positivo ao PAS, com ocorrência frequente de vacuolizações basais PAS negativas, e o surgimento ocasional de grupamentos celulares intravasculares. Nestes, as células que se destacavam da membrana basal do endotélio expressavam progressivamente mais material PAS positivo, o qual, no entanto, em nenhum momento pareceu se tratar de glicogênio. Em relação às glicosaminoglicanas, notamos a presença predominante de ácido hialurônico por todo o mesênquima da região e em outras estruturas como periferia da notocorda, tubo neural e mesoderma lateral. Ocorreu co-expressão de fibronectina e α-actina de músculo liso em células circunjacentes à aorta, na face ventral do vaso. GFAP e BMP-4 são expressas entre as células do tubo neural e em sua periferia, assim como na notocorda do embrião. As lectinas Abrus precatorius, Lens culinarise Ricinus communis mostraram-se positivas principalmente na região subedotelial do assoalho da aorta nos estádios observados neste trabalho. Bandeiraea simplicifolia exibiu pouca marcação na aorta dorsal e a Arachis hypogeae foi negativa. Outras estruturas da região AGM também expressaram resíduos de açúcares revelados por estas lectinas, tais como: notocorda, tubo neural, mesênquima, intestino primitivo e saco vitelínico. Estes resultados acrescentam elementos morfológicos e bioquímicos ao conhecimento sobre a região AGM de embriões de galinha e sobre o endotélio, possivelmente hemogênico, da aorta dorsal. / Nowadays it is known that firsts definitive hematopoietic progenitors arise from endothelium differentiation of dorsal aorta, at Aorta-Gonad-Mesonephros (AGM) site. In order to study those events and cells phenotype of dorsal aorta endothelium in this topographical site, fertilized eggs of Gallus gallus domesticus L. were incubated, from E16 to E25 and to be processed by histotechonology to obtain serial sections of the AGM site. After this, they were stained with Hematoxilin-Eosin, histochemistry to PAS, diastase PAS and Alcian Blue pH 1.0 and pH 2.5, to obtain a better overview and characterization from cells, also, histochemistry to fluorescein lectins and immunofluorescense to surface molecules, cytoeskeleton andextracellular matrix were performed. Our results showed endothelial hypertrophy of the aorta floor in the stages analyzed, which shown positive for PAS, with frequent appearance of PAS negatives basal vacuolizations and an occasional intravascular cell clusters arise of. It was also observed that cells which were separated from endothelium basal membrane shown progressively were more PAS positive which however in any time seems to be glycogen. Regard of glycosaminoglycans we noted the main presence of hialuronic acid for all the mesenchymes site and in others structures like notochord periphery, neural tube and lateral mesoderm. It was observed fibronectin and smooth muscle α-actin co-expression on aorta surrounding walls, at vessels ventral face. GFAP and BMP-4 are express between the cells of neural tube and surrounding it, as well as at embryo notochord. The lectins Abrus precatorius, Lens culinaris and Ricinus communis showed mostly positive expression on the sub endothelium site of the dorsal aorta floor at the stages analyzed in this work. Bandeiraea simplicifolia showed low expression on dorsal aorta and in Arachis hypogeae it was negative. Other structures of AGMs site also expressed sugar residues revealed by these lectins like: notochord, neural tube, mesenchyme, primitive gut and yolk sac.

Haematopoietic stem cells (HSCs) emerge during embryogenesis and maintain hematopoiesis in the adult organism. Qualitative and quantitative assessment of HSCs can only be performed functionally using the in vivo long-term repopulation assay. Due to the lack of such data, little is known about the development of HSCs in the human embryo, which is a prerequisite for the development of new therapeutic strategies. Employing the xenotransplantation assay, I have performed here the spatio-temporal mapping of HSC activity within the human embryo and have shown that human HSCs emerge first in the aorta-gonad-mesonephros (AGM) region, specifically in the ventral wall of the dorsal aorta, and only later appear in the yolk sac, liver and placenta. Human AGM region HSCs transplanted into immunodeficient mice provide long-term high-level multilineage haematopoietic repopulation. These cells, although present in the AGM region in low numbers, exhibit a very high self-renewal potential. A single HSC derived from the AGM region generates around 600 daughter HSCs in primary recipient mice, which disseminate throughout the entire recipient bone marrow and are retransplantable. These findings highlight the vast regenerative potential of the earliest human HSCs and set a new standard for in vitro generation of HSCs from pluripotent stem cells for the purpose of regenerative medicine. I have also established a preliminary immunophenotype of the earliest human HSC. These data will be useful for my future studies on the mechanisms underlying the high potency of human embryonic HSCs and on the characterisation of embryonic HSC niche.

Haematopoietic stem cells (HSC) are invaluable, due to their potential to treat malignant and non-malignant diseases. Modern medicine requires a reliable source of human HSCs (hHSCs) for efficient transplantations, which in many cases cannot be obtained from a single donor. Therefore, the ability to amplify donor hHSCs ex vivo would be an ideal alternative. Past attempts to expand hHSCs in vitro, demonstrated that the protocols developed so far have limited success. My research studied the factors which can affect the optimal culture of transplantable HSCs using a 3D culture system that had previously been used to culture HSCs derived from the aorta-gonad-mesonephros (AGM) region of the mouse embryo. This system involved cell culturing at the gas-liquid interface which is particularly sensitive to mechanical disturbances. To overcome this problem, floating Polypropylene support (rings) were designed and tested and I demonstrated that this was able to prolong aggregate culturing for up to 21 days. Further optimisation tests included altering factors such as oxygen levels, and the presence of antioxidants and apoptosis inhibitors in mouse HSCs culture. I have shown that moderate hypoxia (6% O2) did not affect HSCs in culture, while 2% of O2 led to a significant decrease of HSCs activity. Normoxia resulted in higher reactive oxygen species generation, which would likely be detrimental to cells. However, unexpectedly no improvement in repopulation efficiency of cultured HSCs was achieved by the addition of antioxidant. I also found that when the AGM region was dissociated and co-aggregated in the presence of Rho kinase inhibitor a higher level of repopulation was achieved. In addition, troloxpifitrin-a and p38 inhibitor blocked HSC development without affecting progenitor frequency or the total number of live cells. Subclones of mouse stromal cell line (OP9) were used to create a defined haematopoietic niche for hHSC. Functional screening of these lines in co-aggregate culture re- vealed that 3 of the 34 subclones tested were able to maintain hHSC in culture and repopulate immunodeficient mice at a comparable level to uncultured CD34+ cells. The repopulation in engrafted recipients persisted for over 6 months and showed both myeloid and lymphoid potential. These 3 subclones therefore appeared to create a functional niche for hHSCs and were subsequently used to study the impact of a number of factors including SCF, rock inhibitor, TGFb inhibitor, StemRegenin1 (SR), and prolonged culture technique on hHSC expansion. A significant level of fluctuation between experiments was observed and no definitive conclusions could be drawn. I also attempted to establish stromal cell lines from the human AGM region, more specifically from the ventral (AoV) and dorsal (AoD) regions of the dorsal aorta. Despite attempts to immortalise primary stromal cells, all lines went through a growth crisis. Nevertheless, 30 lines were screened for their ability to support haematopoietic cells in co-aggregate culture with results suggesting that lines derived from AoV expanded haematopoietic precursors more efficiently than AoD lines and OP9 control. Many of the tested lines were able to maintain long-term repopulating human HSCs but the level of repopulation was not as high as that achieved from uncultured CD34+ cells. Unfortunately, these human stromal cell lines have an unstable karyotype which may have an impact on their functional characteristics and they may not represent the nature of the primary cells.

Cette thèse comporte trois parties. La première traite du groupe des automorphismes des courbes modulaires X(N), N premier, sur F_p, p différent de N. On y démontre que, pour p>3 et X(N) ordinaire, ce groupe est exactement PSL_2(Z/NZ). On traite également complètement les cas N=7,11,13. La deuxième partie concerne les courbes optimales. On y montre que N_3(5)=13 et on étudie les propriétés géométriques (groupe d'automorphismes et revêtements) d'une courbe atteignant cette borne. La dernière partie est une extension de la méthode AGM pour le calcul du nombre de points en caractéristique 2 sur une courbe de genre 3 ordinaire et non hyperelliptique. On y démontre la formule reliant les rapports de thêta constantes au produit des valeurs propres du Frobenius unités 2-adiques. On donne un algorithme pour le calcul algébrique des rapports initiaux, un bon modèle de calcul (i.e tel que les calculs s'effectuent dans une extension non ramifiée fixe de Q_2) et on montre comment retrouver le polynôme caractéristique grâce à LLL.

Dans l'embryon de vertébrés l'hématopoïèse se met en place à partir de deux vagues successives de précurseurs hématopoïétiques (PH). Alors que les précurseurs de la première vague, générée dans le Sac Vitellin (SV), présentent des capacités de maintenance et de différenciation réduites, ceux qui sont issus de la seconde présentent toutes les caractéristiques des cellules souches hématopoïétiques (CSH). Elles sont en effet capables de se différencier dans tous les lignages sanguins et permettent d'assurer, à long terme, la reconstitution hématopoïétique de souris létalement irradiées.<br />Le facteur de transcription GATA-3 est exprimé dans l'embryon au cours des phases de détermination et de génération des CSH. Il n'est jamais exprimé aux stades équivalents dans le SV. GATA-3 pourrait jouer un rôle important dans la génération des CSH et dans l'acquisition des propriétés différentes des précurseurs hématopoïétiques des deux sites.<br />Nous avons développé une démarche expérimentale permettant d'effectuer l'analyse fonctionnelle de gènes présentant une expression différente entre les deux sites de génération des précurseurs hématopoïétiques de l'embryon. Nous avons sélectionné l'électroporation in situ pour perturber l'expression génique au moment de la détermination de ces précurseurs, et la transduction rétrovirale pour cibler les PH au moment de leur génération.<br />Nous avons réalisé l'expression ectopique de GATA-3 dans les PH du SV en utilisant l'infection rétrovirale. Nos résultats montrent que GATA-3 est capable d'amplifier et de maintenir des PH immatures. Des tests effectués en parallèle en effectuant l'expression forcée de GATA-5 (naturellement absent du SV), ou la surexpression GATA-1, nous ont permis de conclure à la spécificité de ces effets. De façon remarquable, GATA-3 est également capable d'amplifier une population répondant à un phénotype de type mésodermique/pré-hématopoïétique.<br />En conclusion, nos résultats montrent que GATA-3 pourrait être impliqué dans les phénomènes liés au maintien du contingent de CSH.

This paper investigates the relationship between the theory of belief revision and Lindenbaum-Tarski algebras for propositional logic. The intent is to represent the revision function described by the AGM-postulates algebraically. The AGM theory is based on deductively closed sets, which are characterizable as generated filters in the algebra as well as depictable in the corresponding Hasse diagram. This fact is shown by proving that a partial order is definable for the algebra, that this order is the consequence relation of propositional calculus and that the generated filters are deductively closed. Furthermore, an alternative, but equivalent approach to the AGM theory is introduced, the revision proposed by Katsuno and Mendelzon, which characterizes the deductively closed sets as propositional formulae. This correspondence follows naturally from the behaviour of filters and can be applied without problems to define the functions of the AGM framework in the Lindenbaum-Tarski algebra. The visualization of partially ordered sets as a Hasse diiagram is used to depict an example of a belief revision. Lastly, some combinatorical calculations are introduced to determine the number of possible solution candidates for a belief revision.