Teses / dissertações sobre o tema "Décision de destin cellulaire"
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Kim, Jang-Mi. "Quantitative live imaging analysis of proneural factor dynamics during lateral inhibition in Drosophila". Electronic Thesis or Diss., Sorbonne université, 2022. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2022SORUS585.pdf.
Texto completo da fonteLateral inhibition by Notch is a conserved mechanism that regulates the formation of regular patterns of cell fates1. In many tissues, intercellular Delta-Notch signaling coordinates in time and space binary fate decisions thought to be stochastic. In the context of sensory organ development in Drosophila, it has been proposed that fate symmetry breaking between equipotent cells relies on random fluctuations in the level of Delta/Notch2 (or one of their upstream regulators, e.g. YAP1 in the mouse gut3), with small differences being amplified and stabilized to generate distinct fates. Notch-mediated stochastic fate choices may also be biased by intrinsic, i.e. cell history4, or extrinsic factors. Although lateral inhibition has been extensively studied in many developmental contexts, a detailed in vivo analysis of fate and signaling dynamics is still lacking. Here, we used a quantitative live imaging approach to study the dynamics of sensory organ fate specification in the Drosophila abdomen. The accumulation of the transcription factor Scute (Sc), a key regulator of sensory organ formation in the abdomen, was used as a proxy to monitor proneural competence and SOP fate acquisition in developing pupae expressing GFP-tagged Sc. We generated high spatial and temporal resolution movies and segmented/tracked all nuclei using a custom-made pipeline. This allowed us to quantitatively study Sc dynamics in all cells. Having defined a fate difference index (FDI), we found that symmetry breaking can be detected early, when cells expressed very low and heterogeneous levels of Sc. We also observed rare cases of late fate resolution, e.g. when two cells close to each other accumulate high levels of GFP-Scute before being pulled away from each other. Interestingly, we did not observe a rapid decrease in GFP-Sc levels in non-selected cells right after symmetry breaking. Also, the rate of change of FDI values after symmetry breaking appeared to positively correlate with cell-to-cell heterogeneity in Sc levels. Whether increased heterogeneity is causally linked to symmetry breaking remains to be tested. We next addressed if this stochastic fate decision is biased by birth order (as proposed in the context of the AC/VU decision in worms4) or by the size and geometry of cell-cell contacts (as modeling suggested5). We found that neither appeared to significantly influence Notch-mediated binary fate decisions in the Drosophila abdomen. In conclusion, our live imaging data provide a detailed analysis of proneural dynamics during lateral inhibition in Drosophila
Bonnet, Frédéric. "Choix du destin cellulaire et cinétique du cycle cellulaire : rôle de CDC25B durant la neurogenèse embryonnaire". Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30107/document.
Texto completo da fonteGenerating cell diversity is essential in developmental biology and to preserve tissue homeostasis in adulthood. This results from the choice of stem cells and progenitor cells to commit into a particular fate in response to extrinsic cues and to intrinsic properties. The aim of my PhD was to elucidate the role of the cell cycle in the neurogenesis process (i.e. in neuron generation) using the embryonic chick neural tube as a paradigm. On the one hand, I have developed a new real time imaging strategy to measure the length of the four cell cycle phases in neural progenitors. On the other hand, I performed gain and loss of function experiments of a regulator that control mitosis input, the CDC25B phosphatase, in neural progenitors and showed that this cell cycle regulator promotes neurogenic divisions at the expense of proliferative divisions, thus controlling neuronal production
Lemey, Camille. "Manipulation du destin cellulaire pour améliorer la régénération tissulaire au cours du vieillissement". Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT052.
Texto completo da fonteAging is a complex process which is often punctuated by the appearing of age-related diseases such as arthritis, idiopathic pulmonary fibrosis or osteoporosis, and which is associated with a decrease of regeneration abilities and of adult stem cells number. In 2007, Dr. Yamanaka and his collaborators showed for the first time that human fibroblasts could be converted into pluripotent stem cells by inducing the expression of 4 transcription factors: OCT4, SOX2, KLF4 and c-MYC. In the laboratory, it was showed in 2011 that it is possible to reprogram senescent cells which are accumulating in aging organisms and to differentiate them into rejuvenated somatic cells.In vivo, a total reprogramming would lead to teratomas formation but if the reprogramming process is induced and stopped before getting pluripotent stem cells, we think that it is possible to restore altered cell physiology and to delay tissues aging and its deleterious consequences. Dr. Izpisua Belmonte validated this hypothesis in December 2016. He designed a murine transgenic model which recapitulates the premature aging phenotype of Hutchinson Gilford syndrome and which can be induced to express OCT4, SOX2, KLF4 and c-MYC, and he proved that it is possible to increase mice lifespan and to delay the appearing of pathological aging phenotype. We built a similar murine model and showed that a transient reprogramming can not only increase lifespan, but also delay age-related weight loss and pathological aging phenotype. Moreover, we were able to maintain a higher regenerative capacity until mice death. We also modeled age-related pathologies such as arthritis or idiopathic pulmonary fibrosis in mice which were inducible for the Yamanaka’s transcription factors and we showed that transient reprogramming could prevent damages. This study will have allowed to confirm the importance that cellular reprogramming can have in the fight against aging
Mayeuf, Alicia. "Choix du destin cellulaire des progéniteurs multipotents du somite, chez l'embryon de souris". Paris 6, 2013. http://www.theses.fr/2013PA066495.
Texto completo da fonteThe dorsal part of the somite, the dermomyotome contains multipotent Pax3+ progenitors, which give rise to different cell types such as skeletal muscle, dermal, endothelial, mural and brown adipose cells. The aim of this thesis was to understand mechanisms underlying cell fate decisions in this context in the mouse embryo. We have first shown that the Notch signaling pathway directs multipotent progenitors towards a vascular instead of a myogenic fate, by acting on the Pax3 :Foxc2 genetic equilibrium. To determine if Foxc1, the homologue of Foxc2, is also implicated in this mecanism, we have conditionally deleted both genes in Pax3+ progenitors. We document new phenotypes, including a reduction in vascular, cells, notably endothelial cells in the forelimb, where, surprisingly myogenic cells are also absent, leading to a number of possible hypotheses. Foxc2 is also implicated in the differentiation of brown adipose tissue, which we show is a derivative of Pax3+ cells in the dermomyotome. We have studied the development of this tissue in the embryo and propose a model in two steps, with initial formation of an “undifferentiated adipogenic mass” which subsequently differentiates into brown adipocytes. Gain and loss of function approaches suggest that Foxc1/2 play a role in the control of mitochodrial function during the differentiation of brown adipocytes in the embryo. This role may also be played by Foxc1 in the slow fibers of skeletal muscle where it is specifically expressed in the adult
Bolz, Marianne. "Régulation du destin cellulaire pendant la neurogénèse postnatale : rôle de l'innervation dopaminergique issue du mésencéphale". Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4098.
Texto completo da fonteIn the postnatal and adult mammalian brain neurogenesis persists in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone (SVZ). In the SVZ slowly dividing stem cells give rise to neuroblasts that migrate to the olfactory bulb (OB) where they reach the granule and glomerular cell layer of the OB and differentiate into different interneuron subtypes including a small fraction of dopaminergic interneurons. The discovery of postnatal and adult neurogenesis has changed the view of the plasticity of the brain remarkably and raised the hope for new therapeutical approaches in the field of neurodegenerative diseases. Since in Parkinson’s disease the main motor symptoms are caused by the dopaminergic denervation of the striatum adjacent to SVZ, the understanding of the generation and differentiation of OB dopaminergic neurons has received special attention. Interestingly, the neurotransmitter dopamine itself has been suggested to influence olfactory bulb neurogenesis via direct innervation of SVZ by midbrain dopaminergic neurons. However, data on this topic have been contradictory. In this study, I investigated how dopaminergic innervation influences SVZ neurogenesis and the fate of SVZ progenitors. I combined a 6-OHDA model of dopaminergic denervation in postnatal mice with in vivo forebrain electroporation to specifically label lateral and dorsal SVZ progenitors and to follow their fate in the olfactory bulb
Andriatsilavo, Rakoto Mahéva. "La régulation des cellules souches adultes intestinales de drosophila melanogaster : Comment SPEN influence un destin cellulaire". Electronic Thesis or Diss., Paris 6, 2015. http://www.theses.fr/2015PA066381.
Texto completo da fonteAdult stem cells are non-differentiated cells that maintain tissue homeostasis by supplying differentiated cells while at the same time self-renewing. How is this balance between stem cell state and differentiated state controlled? This question became one of the major interests of the Stem cell research and Translation, mostly due to the potential therapeutic perspectives that it gives. Regarding this effort, this thesis work describes a new function of a gene call split-ends/spen in adult stem cell regulation in Drosophila intestine. SPEN familly is composed by essential genes, which codes conserved proteins from Plants to Metazoa. They are involved in key cellular processes such as cell death, differentiation or proliferation, and are associated with various molecular functions controlling transcriptional and post-transcriptional gene expression. We found that a spen inactivation in Drosophila intestine leads to an abnormal increase in adult stem cells. In this work, by combining genetics tools and in vivo stem cell analysis methods, we could show that Spen works as a key factor of intestinal stem cell commitment and plays a role in their proliferation control. How does genetics programs control cellular identity? In order to investigate the molecular signature of intestinal stem cells and progenitor cells knockdowned for spen, we combined genetics, cell sorting and mRNA sequencing analysis to uncovered Spen target genes regulated in intestinal stem cells. Here, we provide a new function of spen in adult stem cell regulation, which may also shed light on its mode of action in other developmental and pathological contexts
Andriatsilavo, Rakoto Mahéva. "La régulation des cellules souches adultes intestinales de drosophila melanogaster : Comment SPEN influence un destin cellulaire". Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066381/document.
Texto completo da fonteAdult stem cells are non-differentiated cells that maintain tissue homeostasis by supplying differentiated cells while at the same time self-renewing. How is this balance between stem cell state and differentiated state controlled? This question became one of the major interests of the Stem cell research and Translation, mostly due to the potential therapeutic perspectives that it gives. Regarding this effort, this thesis work describes a new function of a gene call split-ends/spen in adult stem cell regulation in Drosophila intestine. SPEN familly is composed by essential genes, which codes conserved proteins from Plants to Metazoa. They are involved in key cellular processes such as cell death, differentiation or proliferation, and are associated with various molecular functions controlling transcriptional and post-transcriptional gene expression. We found that a spen inactivation in Drosophila intestine leads to an abnormal increase in adult stem cells. In this work, by combining genetics tools and in vivo stem cell analysis methods, we could show that Spen works as a key factor of intestinal stem cell commitment and plays a role in their proliferation control. How does genetics programs control cellular identity? In order to investigate the molecular signature of intestinal stem cells and progenitor cells knockdowned for spen, we combined genetics, cell sorting and mRNA sequencing analysis to uncovered Spen target genes regulated in intestinal stem cells. Here, we provide a new function of spen in adult stem cell regulation, which may also shed light on its mode of action in other developmental and pathological contexts
Pontis, Julien. "Rôles d'histones méthyltransférases dans le destin cellulaire : coopération entre des méthyltransférases des lysines 9 et 27 de l'histone H3". Paris 7, 2014. http://www.theses.fr/2014PA077220.
Texto completo da fonteThe genome expression program is regulated by the composition of DNA sequences and the factors that may be associated. These factors may either be transcription factors or cofactors. Cofactors, even if they do not recognize specific DNA sequences, can strongly regulate the expression of the genome. In eukaryotes, some of these cofactors can post-translationally modify structural DNA proteins (histones). These enzymes and their catalized modifications can recruit other cofactors and/or directly regulate chromatin structure allowing fine modulation of the expression of the genome. For example, this allows to control the transcription program during embryonic development or terminal muscle differentiation. Thus, methylation of lysines 9 and 27 of histone H3 (H3K9, H3K27) at gene promoters is essentially associated with transcriptional répression. These lysines are methylated by different specific enzymes called lysine methyltransferases (KMT). The laboratory has previously demonstrated the existence of a complex containing 4 H3K9 methyltransferases (G9A, GLP, and SETDB1 and SUV39H1). During these experiments, the team was able to identify the interaction between H3K9 methyltransferases and H3K27 (PRC2). The main aim of my thesis project was to identify the different genomic targets of KMTs. In these experiments we mainly were able to demonstrate a cooperation between G9A and PRC2 complex
Robert, Rémi. "Étude des mécanismes contrôlant l’expression des gènes HOX et implications pour la génération in vitro de tissus humains". Electronic Thesis or Diss., Sorbonne université, 2023. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2023SORUS399.pdf.
Texto completo da fonteDuring embryogenesis, the formation of the vertebrate body plan depends on the spatial organization of different cell types along the anterior-posterior axis. This process is orchestrated by HOX transcription factors, which are differentially expressed along this axis, conferring positional identity on developing tissues. HOX patterns of expression are initiated by the sequential activation of HOX genes in axial progenitors, a population of stem cells fueling the progressive elongation of the body of developing embryos, forming notably the somites and the spinal cord. In parallel with the progressive induction of this gene family, these progenitors generate increasingly caudal structures, transforming the temporal sequence of activation into spatial domains of expression along the anterior-posterior axis. Nevertheless, the mechanisms that regulate the temporality of this induction and its transformation into spatial domains remain poorly understood, particularly in humans. To address these questions, during my thesis I generated progenitors from human pluripotent stem cells that display the molecular and functional characteristics of axial progenitors. Indeed, we have shown that these progenitors sequentially activate HOX genes and can give rise to organoids recapitulating multiple aspects of the generation and organization of the anterior-posterior axis, such as the formation of somites surrounding a neural tube along which the spatial expression patterns of several HOXs are recapitulated. Using these in vitro-produced axial progenitors, we first demonstrated that the tempo of induction of HOX genes is dynamically modulated by the graded activity of two extrinsic factors, FGFs and GDF11, which are sequentially expressed in the caudal region of vertebrate embryos during development. Then, we showed that 1) activated HOX genes are direct targets of signaling pathways downstream of these factors and 2) that the speed of activation of genes expressed later and later is determined by the duration of pathway activation in axial progenitors, a property of the pathways regulated by intrinsic negative feedback mechanisms. Overall, my results suggest a new model in which the timing of HOX gene activation is an emergent property of the dynamics of signaling pathways downstream of extrinsic factors. In parallel, my studies have led to improved cellular and tissue engineering of trunk cells from human pluripotent stem cells, culminating in protocols for generating the different motor neuron subtypes present along the body axis, and a new organoid model mimicking morphogenesis and the formation of cellular diversity along the human body axis
André-Ratsimbazafy, Marie. "Phenotype plasticity and populations’ dynamics : social interactions among cancer cells". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB032/document.
Texto completo da fonteIt is commonly accepted that tumors arise from cells that escape the homeostatic controls which underlie the healthy histological structure and that cell phenotype is not the result of deterministic biochemical and genetic processes, but rather the stochastic and dynamic outcome of multiple intra- and intercellular regulation networks. This PhD aims to quantitatively study the phenotypic homeostasis of the cell populations and to present an approach to the fundamental question, never heretofore studied, regarding the autonomy versus collective control of cell fate. We studied in the long run, using flow cytometry and in 2D and 3D conditions, the level of expression of CD24 and CD44 of two breast cancer cell lines (SUM149-PT and SUM159-PT). Three phenotypes were isolated (CD24-/CD44+, CD24+/CD44+, CD24-/CD44-), the latter had not previously been documented in the literature. The phenotypic behavior of CD44-low and CD44-high subpopulations has been characterized by assessing their proportion and analyzing the fluorescence map. Thereby, we observed both a periodic behavior of appearance and disappearance of pool of cells characteristics of each cell lines and a phenotypic re-diversification for each subpopulation. Only the resulting population derived from CD24-/CD44- provided the same balance as the original unsorted population. 3D re-diversification process was observed in tumorspheres from CD24-/CD44+ and CD24+/CD44+. The cells CD24-/CD44did not have that potential but nonetheless outlived anoikis. These behaviors suggest that there is an inter-cell coordination regulating the balance of phenotypic proportions. To discover the social rules regulating inter-phenotypic spatial organization, we have set up a reporter of the endogenous variations of CD24 and CD44 and developed a theoretical model of cell interactions. This work has confirmed our hypothesis that inter-cellular social rules are determining the phenotypic expression at both the uni- and multicellular scales
Flick, Florence. "La plasticité de la chromatine oriente le destin des cellules saines et des cellules cancéreuses sur des matrices de faibles rigidités". Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAE020/document.
Texto completo da fonteThe aim of this thesis is to investigate the influence of soft hydrogels on the chromatin plasticity of epithelial PtK2 and cancer cells SW480. On soft hydrogels, the chromatin of PtK2 cells is organized in heterochromatin. The very soft hydrogels direct the cell death by necrosis. On these substrates, the euchromatin maintained by inhibition of HDAC guides the cells into quiescence. These cells transferred on stiff substrate enter in mitosis. A process of metastatic dissemination is developed from cancer cells grown on very soft hydrogels (E20) and stiff surfaces (glass). On the 1st seeding on E20, cells die. The 2nd seeding on E20 shows that cell viability, motility and heterochromatin percentage increase. On the 3rd seeding on E20, survival and motility continue to increase while the heterochromatin percentage decrease. From the 1st- 2nd E20 seeding, cells respond to a heterochromatin-dependent process of metastatic dissemination and from the 3rd-4th E20 seeding to an euchromatin-dependent process
Gothie, Jean-David. "Influence de la signalisation thyroïdienne et du métabolisme mitochondrial sur le choix de destin des cellules souches neurales de la zone sous-ventriculaire chez la souris adulte". Thesis, Paris, Muséum national d'histoire naturelle, 2017. http://www.theses.fr/2017MNHN0023.
Texto completo da fonteThe adult mammalian brain maintains its capacity to generate new cells from neural stem cells (NSCs), mainly localized in two specific brain regions, the hippocampus and the sub-ventricular zone (SVZ). This process, named neurogenesis, results in the production of new neurons and new glial cells (astrocytes and oligodendrocytes). Several signals control NSCs proliferation and differentiation. Among those, thyroid hormones (THs) are involved in NSCs proliferation in the SVZ and in neuronal differentiation. NSC metabolism relies mainly on glycolysis associated with a low mitochondrial activity, whereas mature cells, like neurons and glia, preferentially use oxidative phosphorylation. Changes in NSC metabolism can impact cell fate. As THs play an important part in activating mitochondrial metabolism, I hypothesized that the influence of TH signaling on mitochondrial activity triggers NSC fate choice in the adult SVZ. First, I showed in vivo and in vitro that THs allow NSC determination in neuronal precursors, whereas a short hypothyroidism favors glial determination. Transthyretine, a TH binding protein, is specifically present in the SVZ cells having a neuronal fate, while type 3 deiodinase, a TH inhibitor, is expressed by oligodendrocyte precursor cells (OPCs). These results indicate that THs signaling isdifferentially activated in neuronal and glial cell lineages. I observed that cells adopting a neuronal fate display a greater mitochondrial activity when compared to OPCs, and that TH signaling favors mitochondrial respiration and ROS production in the SVZ cells. Inhibiting the mitochondrial respiratory chain prevents TH-mediated promotion of neuronal determination, proving the need of mitochondrial activation for NSC commitment toward a neuronal phenotype. Besides, it is also known that modifications of mitochondrial morphology (or mitochondrial dynamics) are required for the respiration to increase. Among mitochondrial dynamics, fission is crucial for a good intracellular repartition of energy production, and for cell migration. In the SVZ cells, I showed that, DRP1, the main inducer of mitochondrial fission, is activated by THs mainly in cells adopting a neuronal fate. Thus, THs favor NSC fate choice toward a neuronal phenotype through the activation of mitochondrial metabolism and mitochondrial fission in the adult mouse SVZ
Moussy, Alice. "Caractérisation des premières étapes de différenciation des cellules hématopoïétiques à l'échelle de la cellule unique". Thesis, Paris Sciences et Lettres (ComUE), 2017. http://www.theses.fr/2017PSLEP029/document.
Texto completo da fonteDespite intensively studies, the fundamental mechanisms of cell fate decision during cellular differentiation still remain unclear. The deterministic mechanisms, often based on studies of large cell populations, cannot explain the difference between individual cell fates choices placed in the same environment. The aim of my thesis work is to study the first steps of hematopoietic cell differentiation at the single cell level thanks to transcriptomic, proteomic and morphological analyses. Two differentiation models have been used: T regulatory lymphocytes and human cord blood-derived CD34+ cells. The behavior of individual cells following stimulation has been analyzed. Using time-lapse microscopy coupled to single cell molecular analyses, we could demonstrate that the cell fate choice is not a unique, programmed event. First, the cell reaches a metastable “multi-primed” state, which is characterized by a mixed lineage gene expression pattern. After transition through an “uncertain”, unstable state, characterized by fluctuations between two phenotypes, the cell reaches a stable state. Our observations are coherent with a stochastic model of cell fate decision. The differentiation is likely to be a spontaneous, dynamic, fluctuating and not a deterministic process. The cell fate decisions are taken by individual cells
Pereira, Luis Carlos Gomes. "Modélisation de l’hétérogénéité de la réponse cellulaire aux ligands pro-apoptotiques". Thesis, Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4081.
Texto completo da fonteApoptosis is an essential physiological process through which organisms are able to equilibrate their cell numbers and maintain tissues in healthy and functional conditions. Despite the recent advances in the field, little is known on the molecular mechanisms controlling individual cell decisions to either engage or avoid the activation of this pathway upon cancer treatment, which inevitably impacts on therapeutics development. To obtain a global view of the intervening proteins and their role on cell response dynamics to anticancer drugs, a new and detailed description of the apoptosis pathway at the receptor level was translated into a system of ordinary differential equations. The model was calibrated to single-cell data, from recent experiments on a population of HeLa cells exhibiting a highly heterogeneous response when exposed to the death-inducing ligand TRAIL. The sensitivities of the apoptotic reactions in our model were evaluated using the diversity of experimental behaviors observed in vitro. A series of computational tests and analyses were performed with our model to identify the origins of cell response heterogeneity. New features of the apoptotic pathway emerged from a comparison of different heterogeneity modeling approaches, detecting a set of key reactions to be further expanded. These analyses yield new biological insights and highlights the importance of refining regulation of death receptor complex activity, possibly through Caspase-10 as suggested from new experimental discoveries. This thesis offers a novel framework that can be used to uncover important biological insights using single-cell data of heterogeneous dynamical pathways
Mancini, Laure. "Spatiotemporal control of Neural Stem Cell decisions in the adult zebrafish telencephalon". Electronic Thesis or Diss., Sorbonne université, 2020. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2020SORUS154.pdf.
Texto completo da fonteIn some regions of the adult vertebrate brain, Neural Stem Cells (NSCs) generate fully functional neurons. NSCs are found mostly in quiescence, but can shuttle from quiescence to activation (division). At the population level, the proportion of NSCs dividing at a given time remains constant throughout adulthood and perturbations of NSC activation rate correlate with pathological situations. Also, the spatiotemporal distribution of NSC activation events is expected to impact the homogeneous maintenance of the NSC pools and the locations of neuronal production. What controls the rate and spatiotemporal distribution of NSC activation events remain poorly understood. The adult zebrafish telencephalon is a good model to address these questions. The telencephalon hosts many NSCs and it allow the recording of their behaviors over weeks thanks to an intravital imaging procedure. In this thesis, we have used this model to study the regulation of adult NSCs behaviors from two perspectives. First, we assessed the existence of non-cell-autonomous mechanisms controlling the quiescence-activation balance of the NSC population in space and time. Second, we investigated the relevance of intrinsic heterogeneities on individual NSC behaviors. This work highlighted (i) the importance of NSC geometry for their fate decisions during activation and (ii) the role of their differentiated progeny to locally exert a delayed inhibition, via Notch signaling, to prevent neighboring NSC activation. Using modeling we also show how the lineage-related inhibition maintains NSCs with specific spatiotemporal correlations and can spatially homogenize the distribution of adult-born neurons
Flici, Hakima. "Différenciation et plasticité des cellules souches neurales". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-01070644.
Texto completo da fonteAwada, Rayan. "Application des approches de transcriptomique, de métabolomique et de criblage haut-débit pour démêler les mécanismes impliqués dans l'embryogenèse somatique chez Coffea arabica". Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTG005.
Texto completo da fonteSomatic embryogenesis (SE) is one of the most promising propagation processes for the large-scale dissemination of elite varieties. However, whatever the species considered, research on SE remains essentially empirical and low-throughput, making it difficult to meet the growing demand for plant material, in particular due to the slow technical progress in recent decades. This thesis presents a pioneering work in which two leading groups - Nestlé and CIRAD - have decided to join forces to unravel the molecular mechanisms involved in the key stages of SE in Arabica coffee, one of the most advanced processes, by applying the latest metabolomics and transcriptomics technologies. In parallel, the implementation of a high-throughput screening system for active compounds on SE, that would speed up the optimization of protocols, has not yet been proposed for plant micropropagation.ResultsSeventy samples (14 developmental stages x 5 biological replicates) covering the whole SE process were studied. A robust statistical approach applied to RNA-seq data led to the identification of 6 key developmental switches for the biological success of SE i.e. the mass production of somatic embryos, and revealed the direct influence of environmental drivers. Metabolomics highlighted huge reconfigurations of hormonal contents, primary metabolic pathways and phenolic compounds during the early events of dedifferentiation and redifferentiation. Totipotency reaches its most visible expression at the embryogenic stage when the biochemical pathways related to sugar metabolism are inhibited and, on the contrary, when the expression of genes coding for transcription factors is activated. The study also showed that transcript and metabolite profiles represent discriminant signatures of cell fate. A list of 23 genes and 17 metabolites that mark the success of the different developmental phases has been identified, including the embryogenic callus stage, so strategic due to its position at the Dedifferentiation-Redifferentiation interface. In parallel, we succeeded in reproducing on a pilot scale the differentiation of somatic embryos from liquid cell suspensions in a miniaturized system compatible with an automated platform and thus allowed the screening of 4 epigenetic regulators (HDACi) at different concentrations, bringing a proof of concept of the feasibility of nutrient media high-throughput optimization. For all SE key developmental stages, deciphering the main molecular mechanisms as well as the identification of specific molecular markers offers new perspectives for a detailed understanding of this regeneration phenomenon and its rational optimization. Strategies are proposed for the validation of candidate markers and the industrialization of the high-throughput screening system. A combination of both -omics and automation approaches is proposed for rational and more efficient protocol optimization, allowing the SE processes to support the very large-scale dissemination of genetic progress in coffee
Atine, Jean-Charles. "Méthodes d'apprentissage flou : application à la segmentation d'images biologiques". Toulouse, INSA, 2005. http://eprint.insa-toulouse.fr/archive/00000272/.
Texto completo da fonteThe presented works have for objective to help the biologists in the diagnosis of the cellular viability by using some methods of classification. Our work announces a strategy of classification allowing to building partition of images of cells coming from an optical microscope. We classify automatically the cells by operating the segmentation on images using the developed algorithm T-LAMDA. A statement concerning the existing classification methods, the color space and the resistance to noise, allows to finding the structure the most adapted to our study. The comparative analysis of various methods (of which LAMDA and T-LAMDA methods), allows us to put in evidence the most appropriate for the classification of cells subjected to the blue of methylene solution. We propose some supervised algorithms based on LAMDA to show if the way of treating the data influence the result. The T-LAMDA algorithm, based on the decision trees, shows itself the best adapted for our study and so gives more precise results than other methods, with a shorter time of execution. We suggest learning by using the CELCA application, Cell Classification Application, which uses the developed T-LAMDA algorithm. The software takes care of calculations of the kinetics, according to the images which respect to a well defined protocol. Time for treating 117 images is 6 '47'' minutes, what is widely below the time taken by biologists to count the cells
Naylor, Peter. "Du phénotypage cellulaire à la classification de lames digitales : Une application au traitement du cancer du sein triple-négatif". Thesis, Paris Sciences et Lettres (ComUE), 2019. http://www.theses.fr/2019PSLEM051.
Texto completo da fonteThe rise of digital pathology and with it the challenges of histopathology analysis have been the focus of a worldwide effort in the overall fight against cancer. In parallel, the recent success of automated decision-making, machine learning, and specifically deep learning, have revolutionised the basis of research as we know today. In this thesis, we tackle the prediction of treatment response in triple-negative breast cancer patients with two different approaches that reach similar outcomes. The first line of approach, based on the recent success of computer vision, extracts learned features from the data in order to perform classification. The second line of approach forces the information flow to pass through nuclei segmentation. In particular, it allows the incorporation of high-resolution information on to a lower resolution overview. Yet while this approach is more appealing as it is based on the analysis and quantification of a precise biological element, nuclei segmentation is troublesome. While solving the task of nuclei segmentation with deep learning, we propose a new formulation for nuclei segmentation which excels at separating touching objects
Duchesne, Ronan. "Erythroid differentiation in vitro under the lens of mathematical modelling". Thesis, Lyon, 2019. http://www.theses.fr/2019LYSEN082.
Texto completo da fonteDuring the past several years, several independent studies have shown that cell differentiation is accompanied by anincrease of the level of variability of gene expression. Hypothesizing that gene expression variability is a driver of celldifferentiation, our group has identified three chemical drugs (called artemisinin, indomethacin and MB3) whichinfluence both the extent of this variability and the number of differentiated cells in a culture of avian erythroidprogenitors.This thesis follows these observations, and is divided in two parts. First, we define a mathematical model ofavian in vitro erythroid differentiation and confront it to our experimental data, in order to disentangle the effect of thedrugs on cell proliferation, differentiation and death. Since the comparison of parameter values between the treated anduntreated conditions requires precise parameter estimates, an important part of the design of our model is theidentifiability of its parameters. We prove that the drugs which decrease gene expression variability (artemisinin andinndomethacin) also decrease the differentiation rate of the cells, and that the drug which increase variability (MB3)also increases the differentiation rate.Then, observing significant variability in the outcome of our in vitro differentiation experiment, we motivate thedesign of a mixed effect model of erythropoiesis, in which each replicate of the experiment is an individual characterizedby its own parameter values. Mixed effect models are a type of statistical models in which the fixed parameters arereplaced by distributions of random variables, in order to describe the repeated measurement of the same process ondifferent individuals from the same population. Each individual is then described by its own parameter values, and thepopulation is described by the distribution of parameter values across all individuals. We demonstrate the unidentifiabilityof this mixed effect model, and we finish by exploring ways of rendering it identifiable, using experimental design andmodel reduction
Mazurier, Nicolas. "Etude des mécanismes de maintenance et de spécification des cellules souches et progénitrices de la rétine du xénope". Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00980574.
Texto completo da fonteCaldarelli, Paolo. "On the role of mechanical forces in embryonic self-organization". Electronic Thesis or Diss., Sorbonne université, 2021. http://www.theses.fr/2021SORUS189.
Texto completo da fonteDuring embryonic development, cells divide, migrate, rearrange, acquire different fates while organizing into a properly shaped organism. The regulation of these events is increasingly recognized to be controlled by self-organizing mechanisms. Following the seminal work of Alan Turing, who postulated, in his reaction-diffusion model, that self-organization could be controlled by the interaction between molecules, subsequent studies have focused on the identification of signaling molecules fulfilling Turing’s criteria. However, mechanical forces are generated and propagated at the tissue-scale level during morphogenesis, yet the possibility that they might act as signals in embryonic self-organization is largely underexplored. The gastrulating avian embryo, which is highly amenable to both live imaging approaches and mechanical perturbations, represents a great model to investigate the role of mechanical forces during development. Furthermore, classic experiments have demonstrated the highly regulative and self-organizing nature of early avian development: when the early epithelial disk (blastoderm) is bisected, fully formed embryos emerge from each separated part. Although recent work performed in the lab has drawn a precise mechanical picture that shapes the embryo at this stage, their role in regulating and self-organizing the embryo remains elusive, and it is the subject of this Ph.D. thesis. In collaboration with a physicist, we first formulated a mathematical model that accounts for the steady pattern of forces observed at the margin between the embryonic and extraembryonic region of the embryo. The model is based on the hypothesis that tissue mechanics at the margin self-organizes in analogy to a mechanical Turing system: tissue contractility acts as a local activator and tissue tension as a long-range inhibitor. We obtained unique predictions, which we tested experimentally to validate our model and ultimately explore the link between mechanical forces and gene expression. We found that modulation of tissue contractility at the margin alters the normal expression of Gdf1, a key morphogen in the formation of the embryo, and results in the formation of ectopic primitive streaks (primary body axis). We then perturbed the embryo mechanically. Using time-lapse imaging and laser ablation, we could orient and precisely bisect the early blastoderm. We found that in anterior halves, tissue contractility can ectopically initiate Gdf1 expression and primitive streak formation. Subsequently, to further explore the feedback between tissue mechanics and gene expression, we focused on the posterior bisected half where Gdf1 is endogenously expressed. We showed that after a few hours from the cut, the mechanical forces rescale according to the new size of the margin along with the expression domains of Gdf1. Moreover, we also found that the expression of selected embryonic territories markers follows the rescaling of the margin, suggesting an active role of tissue mechanics in allocating cell fate during development. Lastly, we showed that ectopic primitive streaks could form by placing a physical obstacle at the margin, following a prediction whereby ectopic friction is added to the motion of the tissue at the margin. This last result strongly argues against molecular diffusion as the driver of self-organization and rules out spurious events in the formation of ectopic embryos upon bisection (i.d. wound healing). Thus, this work uncovers the role of mechanical forces as signaling factors during embryonic development and demonstrates that tissue mechanics at the margin of the embryo self-organizes and underlies embryonic regulation in amniotes
Judge, Valentine. "Apport de l’apprentissage automatique pour la modélisation et l’analyse des changements d’occupation du sol : application au développement urbain de la zone frontalière franco-allemande". Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCC011.
Texto completo da fonteUrban development can take different forms or features, depending on its geographical location and its socio-economic, political and cultural context. Nevertheless, the overall action relies on one fundamental principle: building construction in order to give people housing. Therefore, the main objective of this research is to determine whether an underlying universal aspect of the urban development process can be distinguished from a specific one, being the reflect of local specificities. Specifically, this research analyzes the land use change on the French-German cross-border area. Indeed, the border context enhances the difference within this territory. Nonetheless, the internal European border importance as a separation is getting lower while European Union agreement and cooperation are getting stronger. Consequently, we tend to question a potential homogeneity of such area according the urban development analysis. To gain a better understanding of the urban development in the French-German cross-border area, a specific method using a decision tree (DT) process to generate and calibrate urban transition rules for cellular automata (CA) has been developed. In order to define CA rules, the learning algorithm is provided with data of land use, from 1990 and 2006, accessibility to the main urban area and country location. The findings demonstrate that the rule set identified rules, which are constrained at different levels: from the initial land use state needed for urbanization to the geographical location in a specific country. The analysis therefore shows rules specific to France or Germany, as well as rules free from any state location constraints, which characterize a cross-border urbanization process. The latter is more influenced by the location toward main urban areas. Proper neighborhood and internal characteristic of urbanized cells depending of the nature of the rule (French, German or Cross-border) are explicitly defined. In conclusion, this research contribution can be summarized according to the following three orientations: (1) from a theoretical point of view, which propose to identify urban processes degree of universality, (2) from a thematic outlook, describing the influence of the urban development process location on the border area, (3) from a methodological point of view, pairing DT and AC to automatically design and calibrate the urban development model used in this research work
Agbossou, Igor. "Modélisation et simulation multi-agents de la dynamique urbaine : application à la mobilité résidentielle". Phd thesis, Université de Franche-Comté, 2007. http://tel.archives-ouvertes.fr/tel-00924741.
Texto completo da fonteHanna, Eve. "Les thérapies innovantes : une révolution médicale et un tsunami financier". Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0622/document.
Texto completo da fonteThe objectives of this thesis were to identify the magnitude of the ATMPs pipeline, to assess the budget impact of ATMPs and to suggest new funding models for ATMPs in order to help decision-makers to anticipate the hypothetical short and medium term budget impact of such products. The magnitude of ATMPs pipeline was evaluated by identifying the number and characteristics of ATMPs clinical trials in 3 worldwide clinical trials databases. A large number of ATMPs are in development (939 clinical trials) and may successfully reach the market. Overall, the results showed that the number of ATMPs clinical trials has been consistently growing over the past 15 years. The budget impact of ATMPs was assessed. Markov models were developed to assess the cost-effectiveness and budget impact for ATMPs using 5 efficacy scenarios in Parkinson disease, Alzheimer’s disease and heart failure. Then, an estimation of the budget impact of 35 ATMPs was conducted suggesting that an ATMP can cure all patients. We have shown in this chapter that a cost-effective ATMP may be unaffordable; payers will not be able to pay upfront the costs of all ATMPs. The traditional funding models may not be adaptable for ATMPs. The proposed funding models for innovative high-cost therapies were identified through a literature review, discussed during a consensus meeting and an optimal funding model for ATMPs was recommended.Finally, health policy recommendations for the stakeholders – patients, physicians, payers and manufacturers – are presented. These recommendations aim to help to ensure patient access to innovation while maintaining the sustainability of healthcare system
Demers, Simon-Pierre. "La dérivation de cellules souches embryonnaires chez le rat, Rattus norvegicus". Thèse, 2009. http://hdl.handle.net/1866/6402.
Texto completo da fonteMalleshaiah, Mohan. "Molecular mechanisms for a switch-like mating decision in Saccharomyces cerevisiae". Thèse, 2011. http://hdl.handle.net/1866/5268.
Texto completo da fonteEvolution has resulted in numerous innovations that allow organisms to maximize their fitness by choosing particular mating partners, including secondary sexual characteristics, behavioural patterns, chemical attractants and corresponding sensory mechanisms. The haploid yeast Saccharomyces cerevisiae selects mating partners by interpreting the concentration gradient of pheromone secreted by potential mates through a network of mitogen-activated protein kinase (MAPK) signaling proteins. The mating decision in yeast is an all-or-none, or switch-like, response that allows cells to make accurate decisions about which among potential partners to mate with and to filter weak pheromone signals, thus avoiding inappropriate commitment to mating by responding only at or above critical concentrations when a mate is sufficiently close. The molecular mechanisms that govern the switch-like mating decision are poorly understood. In this thesis I demonstrate that the switching mechanism arises from competition between the MAPK Fus3 and a phosphatase Ptc1 for control of the phosphorylation state of four sites on the scaffold protein Ste5. This competition results in a switch-like dissociation of Fus3 from Ste5 that is necessary to generate the switch-like mating response. Thus, the decision to mate is made at an early stage in the pheromone pathway and occurs rapidly, perhaps to prevent the loss of the potential mate to competitors. We argue that the architecture of the Fus3–Ste5–Ptc1 circuit generates a novel ultrasensitivity mechanism that resembles “zero-order ultrasensitivity”, which is robust to variations in the concentrations of these proteins. This robustness helps assure that mating can occur despite stochastic or genetic variation between individuals. I then demonstrate that during the mating response, an early event of Ste5 recruitment to plasma membrane is ultrasensitive and that it is generated by dephosphorylation of eight N-terminal phosphosites on Ste5 by the phosphatase Ptc1 when associated with Ste5 via the polarization protein Bem1. Interference with this mechanism results in loss of ultrasensitivity and reduced amplitude and therefore fidelity of the pheromone signaling response. These changes are reflected in reduced fidelity and accuracy of the morphogenic mating response. Polarized assembly of signaling protein complexes at the plasma membrane surface is a general theme recapitulated in all organisms from bacteria to humans. Such complexes can increase the efficiency, fidelity and specificity of signal transduction. Together with our previous findings, our results demonstrate that ultrasensitivity, accuracy and robustness of the pheromone response occurs through regulation of the stoichiometry of phosphorylation of two clusters of phosphosites on Ste5, by Ptc1, one cluster mediating ultrasensitive recruitment of Ste5 to the membrane and the other, ultrasensitive dissociation and activation of the terminal MAP kinase Fus3. The role of Ste5 as a direct modulator of a cell-fate decision expands the functional repertoire of scaffold proteins beyond providing specificity and efficiency of information processing. Regulation of dynamic signal-response characteristics through such modular regulation of clusters of phosphosites may be a general means by which cell fate decisions are achieved. Similar mechanisms may govern cellular decisions in higher organisms and be disrupted in cancer. Finally, in a related theme, I present the discovery of a novel mechanisms by which the threshold of pheromone response is controlled by a nutrient-sensing pathway, thus adjusting the set-point at which the quantity and quality of nutrients available in the environment set the threshold of pheromone at which yeast will mate. The regulatory subunit of protein kinase A (PKA), Bcy1, a key component of a nutrient sensing signaling network, directly interacts with the α subunit of G-protein, Gpa1, the primary effector of the pheromone signaling network. The Bcy1-Gpa1 interaction is enhanced when cells are grown in their ideal carbon source glucose, lowering the threshold concentration at which the mating response is activated. Disruption of Bcy1-Gpa1 interaction or Bcy1 deletion increased the threshold concentration for the mating response. We argue that by adjusting their sensitivity, yeast can integrate pheromone stimulus with glucose levels and prioritize decisions to survive in a nutrient-starved environment or to continue their sexual cycle by mating.