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Modulation De L'expression Du Gène De La Sous-Unité Α5 De L'intégrine Α5β1 Par Les Composantes De La Matrice Extracell

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Modulation De L'expression Du Gène De La Sous-Unité Α5 De L'intégrine Α5β1 Par Les Composantes De La Matrice Extracell Modulation de l’expression du gène de la sous-unité α5 de l’intégrine α5β1 par les composantes de la matrice extracellulaire durant la cicatrisation de l’épithélium cornéen Thèse Jennifer Lake Doctorat en biologie cellulaire et moléculaire Philosophiae Doctor (Ph.D.) Québec, Canada © Jennifer Lake, 2015 ii RÉSUMÉ Dès les premières heures suivant une lésion à l’épithélium cornéen, d’importantes quantités de fibronectine (FN) sont sécrétées dans la membrane basale, tandis que l’expression des laminines (LMs) et des collagènes (principalement le type IV) diminue temporairement pour réapparaitre une fois la lésion recouverte. L’intégrine α5β1 joue un rôle majeur dans la cicatrisation cornéenne en favorisant l’adhésion et la migration des cellules épithéliales de cornées (CEC) sur la matrice temporaire de FN. Notre laboratoire étudie la modulation d’expression du gène codant pour la sous-unité α5 par les composantes de la matrice extracellulaire (MEC) durant la cicatrisation de l’épithélium cornéen. Des travaux antérieurs réalisés dans notre laboratoire ont permis de démontrer que la FN exerce une influence positive sur l’activité transcriptionnelle du promoteur du gène α5, tandis que la LM exerce une influence négative dans des CEC de lapins. Toutefois, l’étude des influences individuelles des collagènes ou des effets combinés des matrices complexes n’avait jamais été entreprise à ce jour. Les travaux présentés dans cette thèse ont permis de démontrer que les matrices extracellulaires complexes, composées de FN et de différents types de collagènes, exercent une influence positive sur l’expression du gène α5 dans des CEC humaines. Ces influences de la MEC résultent de modifications dans l’expression et les activités de liaison à l’ADN des facteurs de transcription NFI, Sp1, AP-1 et Pax-6. À l’inverse, les matrices simples de collagènes exercent une influence négative sur l’expression du gène α5 dans les CECs ce qui suggère qu’une des multiples actions des collagènes pourrait être de ralentir la migration et la prolifération des cellules épithéliales afin de permettre leur différenciation dans les couches supérieures de l’épithélium cornéen. Nous avons également démontré la présence d’une région distale conservée de 300 nucléotides située en amont des gènes codant pour les sous-unités d’intégrines α3, α5, α9 et αv. Cette région conservée porte plusieurs éléments de régulation (positifs et négatifs) qui contribuent à la modulation fine de l’expression du gène α5. Outre les gènes pour certaines intégrines, la MEC modifie profondément l’expression de plusieurs gènes codant, entre- autre, pour des métalloprotéinases matricielles (MMPs) et diverses composantes de la MEC. iii iv ABSTRACT Upon corneal injury, it is the massive secretion of fibronectin (FN) that characterizes the very first changes occurring in the basement membrane (BM) while in the meantime laminin (LM) and collagens (mostly type IV) temporarily disappear and then sequentially reappear once the denuded corneal area is completely covered. The FN binding integrin α5β1 plays a major role in corneal wound healing by promoting epithelial cell adhesion and migration over the temporary FN matrix. Over the past few years, our laboratory investigated the mechanisms by which the extracellular matrix (ECM) components may alter the expression of the α5 integrin subunit gene during corneal wound healing. While FN was found to positively regulate the expression of the α5 gene promoter, LM surprisingly repressed its transcription in rabbit corneal epithelial cells. However, the individual influences of collagens, or the combinatorial influence of a more complex tissue- engineered ECM had yet to be determined. In this thesis, we demonstrated that the reconstructed ECM, which is enriched in several types of collagens and FN, exerts a positive influence on the expression of the α5 gene in human corneal epithelial cells as a result of alterations in the expression and DNA binding of the transcription factors NFI, Sp1, AP-1 and Pax-6. On the other hand, collagens most usually acted negatively on the expression of the α5 integrin gene in corneal epithelial cells (CECs). One can then speculate that a particularly important function of the corneal BM collagens would consist to inform CECs that cell migration is no longer required, allowing them to differentiate vertically into suprabasal epithelial cells. We also demonstrated that a 300 bp conserved 5’- distal region present in the α3, α5, α9 and αv integrin subunit gene promoter sequences contains several target sites for positive and negative transcription factors that may prove important for fine-tuned regulation of α5 gene transcription. In addition, the ECM components also cause important changes in the expression of other genes, such as those encoding matrix metalloproteinases (MMPs) and various ECM components. v vi Table des matières RÉSUMÉ ............................................................................................................................................................. iii ABSTRACT ......................................................................................................................................................... v Table des matières ............................................................................................................................................. vii Liste des tableaux ............................................................................................................................................. xiii Liste des figures ................................................................................................................................................ xv Liste des abréviations ....................................................................................................................................... xix Remerciements .............................................................................................................................................. xxvii Avant-propos ................................................................................................................................................... xxix Chapitre I : Revue de la littérature ....................................................................................................................... 1 1. Introduction ..................................................................................................................................................... 1 1.1. Le globe oculaire humain ......................................................................................................................... 2 1.2. La cornée ................................................................................................................................................. 4 1.2.1. L’épithélium cornéen ........................................................................................................................ 5 1.2.2. Le stroma cornéen et la membrane de Bowman ............................................................................ 13 1.2.3. L’endothélium cornéen et la membrane de Descemet ................................................................... 16 1.3. Maladies de la cornée : Syndromes de déficience en cellules souches limbiques ................................ 17 1.3.1. Les traitements ............................................................................................................................... 18 1.3.1.1. Greffes de limbe et de cornée ................................................................................................. 18 1.3.1.2. Greffe d’épithélium cornéen cultivé in vitro ............................................................................. 20 1.3.1.3. Cornées reconstruites in vitro par génie tissulaire................................................................... 21 1.4. Cicatrisation cornéenne ......................................................................................................................... 30 1.4.1. Les étapes de la cicatrisation de l’épithélium cornéen ................................................................... 30 1.4.1.1. Phase latente .......................................................................................................................... 32 1.4.1.2. Migration cellulaire .................................................................................................................. 33 1.4.1.3. Prolifération et différenciation cellulaire ................................................................................... 34 1.4.1.4. Adhésion cellulaire .................................................................................................................. 36 1.4.2. Cicatrisation du stroma cornéen ..................................................................................................... 38 1.4.3. Cicatrisation de l’endothélium cornéen ........................................................................................... 39 1.4.4. Modèles pour l’étude de la guérison des plaies cornéenne ............................................................ 40 1.4.5. Facteurs modulant la cicatrisation de la cornée ............................................................................. 46 1.4.5.1. Les facteurs de croissance, les cytokines et les facteurs neuraux .......................................... 46 vii 1.4.5.2. Les sérine-protéases et les métalloprotéinases matricielles (MMPs) .....................................
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