Pathologies des hélicases et vieillissement précoce : modèle d'étude par dérivation de cellules souches pluripotentes induites (iPS)

Abstract : Helicases process the double-stranded DNA dissociation. They are involved in replication, DNA repair and maintenance of telomeres. In human, 3 helicases display mutations responsible for clinical syndromes: WRN for the Werner syndrome, BLM for the Bloom syndrome and RECQL4 for the Rothmund-Thomson syndrome. All these diseases cause premature ageing and high risk of cancer. Molecular and cellular mechanisms involved in these diseases are not well defined. Particularly, little is known concerning the link between genomic instability and ageing. During this project, we used blood samples and skin biopsies of affected patients to generate models by reprogramming cells to induced pluripotent stem cells (iPSCs). These cells have the advantage of self-renewing and theoretically could be differentiated in all cell types. At the same time, an iPSC senescence control was performed from cells of a Hutchinson-Gilford Progeria syndrome patient. iPSCs were characterized for pluripotency. In the aim of recapitulate these pathologies in vitro, we identified sets of cellular and molecular phenotypes. We also engaged differentiation of iPSCs in cell pathways closed to the affected tissues in vivo. Finally, we studied the genomic stability of iPSCs and derived cells. We observed that Bloom cells are susceptible to frequent recombinations and are characterized by a genome instability through all studied cell types. Werner cells showed an instability of telomeres length. Finally, all premature ageing diseases displayed mitochondrial defects.
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Vincent Gatinois. Pathologies des hélicases et vieillissement précoce : modèle d'étude par dérivation de cellules souches pluripotentes induites (iPS). Médecine humaine et pathologie. Université Montpellier, 2017. Français. ⟨NNT : 2017MONTT042⟩. ⟨tel-01690758⟩

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