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Contribution des gènes des loci 5q11 et 11q23 à la multiciliogenèse et régulation de l’équilibre mucociliaire de l’épithélium des voies respiratoires au cours de la régénération in vitro

Abstract : Airways are lined by a pseudostratified mucociliated epithelium which is mainly composed of basal, goblet and multiciliated cells harboring hundreds of motile cilia at their apical part. Their coordinated beating allows the expulsion of inhaled particles that get trapped in the mucus. Following tissue lesions, the epithelium must regenerate, and maintain a strict balance between proportions of each cell type. In chronic respiratory diseases, such as cystic fibrosis, chronic infections and inflammation lead to tissue repair defects and airway epithelium remodeling, characterized by secretory hyperplasia and progressive loss of multiciliated cells.My PhD project aimed to improve our knowledge about mechanisms controlling the airway epithelium regeneration, which is a required step to the development of future regenerative therapies. We have used an in vitro cell culture model of human and murine airway epithelia and have performed single-cell RNA-sequencing approaches.Multiciliated cells differentiate from progenitors to generate multiple motile cilia, a process called multiciliogenesis. My host laboratory has previously demonstrated that this process is controlled by both miR-34b/c and miR-449a/b/c microRNAs, together with CDC20B, miR-449 host gene which is localized in the 5q11 human genomic locus. This 5q11 locus was further established as a hot spot of multiciliogenesis regulators.In a first part of my work, we identified and characterized variants of miR-34/449 microRNAs, called isomiR-34/449. These isomiRs, sharing certain functions with their “canonical” counterparts, also have distinct functions, and thus represents an additional mechanism for regulating multiciliogenesis.In a second part of my thesis, I have demonstrated, by analogy to the 5q11 locus, that the 3 nearest genes (C11orf88, LAYN and BTG4) located in the genomic region of miR-34b/c (11q23 locus) were also expressed in multiciliated cells. Importantly, C11orf88, a protein of unknown function, was highly and exclusively expressed in motile cilia of multiciliated cells, suggesting a role in ciliary function. This 11q23 locus may constitute an additional hot spot of multiciliogenesis regulators.Finally, a last part of my work contributed to established a transcriptomic cartography of distinct cell types during the constitutive steps of airway epithelium regeneration. This allowed us to (1) identify a new differentiation trajectory from goblet to multiciliated cells and (2) reveal that proliferation and differentiation cell culture media yield significant differences on epithelia morphology, cell composition and on the gene expression profiles of these distinct cell types.Altogether data gathered during my PhD work have allowed to unravel new molecular mechanisms involved in airway epithelium regeneration, and has provided novel candidate genes as potential regulators of multiciliogenesis.
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Amélie Cavard. Contribution des gènes des loci 5q11 et 11q23 à la multiciliogenèse et régulation de l’équilibre mucociliaire de l’épithélium des voies respiratoires au cours de la régénération in vitro. Biologie moléculaire. Université Côte d'Azur, 2020. Français. ⟨NNT : 2020COAZ6006⟩. ⟨tel-03200434⟩

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