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Evaluation du rôle de la niche hématopoïétique dans l'induction des syndromes myélodysplasiques : rôle de dicer1 et du stress oxydatif

Abstract : Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) oligoclonal diseases leading to dysplasia, blood cytopenia and evolution to acute leukemia. Numerous mutations in genes involved in epigenetic regulation are responsible of MDS genesis. But recently, studies show that medullar microenvironment, particularly mesenchymal stromal cells (MSC), could induces and propagates a truly MDS suggesting a narrow communication between HSC and this niche. Dicer1’s (type III RNAse implicating in microRNA processing) invalidation in murine osteoblastic progenitors induces a MDS with sign of dysplasia.In this work, we have confirmed the under expression of Dicer1 in MDS mesenchymal stromal cells from total bone marrow and cultured MSC. Dicer1 down regulation leads to a deregulation of miRNome profile in MDS MSC highlighted by transcriptomic approaches. We found a potential therapeutic target: miR-486-5p which is constantly overexpressed in MDS MSC. Extracellular vesicles (EVs) could be a possible way for MSC to influence HSC fates. Those EVs are heterogeneous are could be characterized by their sight. We mainly focused on small EVs (sEVs) containing the exosomal fraction known to be able to carry miRNA, mRNA and proteins. We found that miR-486-5p is carry from MSC to the HSC. Transcriptomic analyses of HD HSC overexpressing miR-486-5p are ongoing. Moreover, in a co-incubation model (sEVs and healthy donor (HD) HSC), sEVs coming from MDS MSC induced apoptosis, oxidative stress and DNA damages.Moreover, iron overload seen in MDS patients is also able to induce DNA damages and oxidative stress. Deferasirox (DFX), an iron chelator, has shown an erythropoiesis improvement in MDS patients. Using an erythroid differentiation model with iron overload, we have observed that low dose of DFX induce a better proliferation of erythroid progenitors (less apoptosis and more cycling cells) due to NF-κB activation. This activation is due to a decrease of reactive oxygen species level in relation to a decrease of the labile iron pool.Finally, we have used medullar microenvironment properties to establish a murine model of MDS. Indeed, MDS HSC incapacity to reconstitute a pathological hematopoiesis in immunocompromised mice suggests that MDS HSC need an extrinsic support from the microenvironment. We have engineered a MDS patient derived xenograft (PDX) model by intra-tibial co-injection CD34+ cells with MSC. All mice engrafted et we have follow the clonal evolution over mice generation in the different subset of myeloid progenitors. (common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP) and megakaryocyte–erythroid progenitor (MEP)). Our model is stable over generations with persistence of the initial founding clone.In conclusion, this work confirms the preponderant role of the medullary microenvironment in the genesis and physiopathology of myelodysplastic syndromes and opens the way to new therapeutic possibilities.
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Mathieu Meunier. Evaluation du rôle de la niche hématopoïétique dans l'induction des syndromes myélodysplasiques : rôle de dicer1 et du stress oxydatif. Santé. Université Grenoble Alpes, 2018. Français. ⟨NNT : 2018GREAS014⟩. ⟨tel-02372468⟩

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