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MODELISATION PATHOLOGIQUE DES MALADIES MONOGENIQUES PAR L'UTILISATION DES CELLULES SOUCHES EMBRYONNAIRES HUMAINES. PREUVE DE CONCEPT APPLIQUEE A LA DYSTROPHIE MYOTONIQUE DE TYPE 1

Abstract : Among their promising applications, human embryonic stem cells lines (hES) have huge potential to improve the understanding of molecular and cellular mechanisms involved in the development of monogenic diseases. This application of modeling pathologic became possible using hES cell lines carrying the causal mutation of a monogenic disease, obtained during pre-implantation diagnosis. The team where I did my thesis work demonstrated that hES cell lines and their progeny, carrying the causal mutation in myotonic dystrophy type 1 (DM1), expressing the molecular defects characteristic of the pathology, allowing more relevant analysis than primary cultures derived from biopsies of patients and validates the use of this cell model. In this context, in the first part of my thesis, my goal was to develop culture conditions for hES cell differentiation into normal and mutant neural lineage in order to obtain homogeneous populations of neural progenitors and neural stem cells and to characterize their phenotypic and fonctional preperties. Next, using a transcriptomic method, I compared the expression profile of neural progenitors to another homogeneous population of mesenchymal precursors. Thus, I identified genes and signaling pathways specific to each of these populations. (Article 1). In the second part of my work, my contribution to the pathological modeling of DM1 was to use these mutant neural progenitor cells and neural stem cells to explore the pathophysiological mechanisms involved in neurological symptoms observed in this pathology. Thus, I have identified a cell signaling pathway defects in mTORC1 pathway based on the observation that NSC cells carrying DM1 mutation proliferated more slowly than control cells (Article II).At last, I also studied the expression of Tau protein, a protein involved in Alzheimer's disease and I have highlighted changes suggesting impairement of axonal transport in neurons derived from hES cell lines mutant. These results, together with those performed in the team, can provide proof of concept for the benefit of such a cell model for modeling disease monogenic diseases.
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https://tel.archives-ouvertes.fr/tel-00545797
Contributor : Jérôme Denis <>
Submitted on : Sunday, December 12, 2010 - 9:06:53 PM
Last modification on : Friday, October 23, 2020 - 4:42:55 PM
Long-term archiving on: : Sunday, March 13, 2011 - 2:41:22 AM

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Jérôme Alexandre Denis. MODELISATION PATHOLOGIQUE DES MALADIES MONOGENIQUES PAR L'UTILISATION DES CELLULES SOUCHES EMBRYONNAIRES HUMAINES. PREUVE DE CONCEPT APPLIQUEE A LA DYSTROPHIE MYOTONIQUE DE TYPE 1. Biologie cellulaire. Université d'Evry-Val d'Essonne, 2010. Français. ⟨tel-00545797⟩

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