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A Study of Fibroblast-Mediated Contraction in Ocular Scarring: Gene Expression Profiling and the Role of Small Gtpases in Matrix

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A Study of Fibroblast-Mediated Contraction in Ocular Scarring: Gene Expression Profiling and the Role of Small Gtpases in Matrix A study of fibroblast-mediated contraction in ocular scarring: gene expression profiling and the role of small GTPases in Matrix Metalloproteinase 1 (MMP1) regulation He Li This thesis is submitted to University College London for the degree of Doctor of Philosophy in Cell Biology 2017 Supervisors: Dr. Maryse Bailly Prof. Sir. Peng Tee Khaw UCL Institute of Ophthalmology 11-43 Bath Street, London EC1V 9EL 1 Declaration I, He Li, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Understanding the molecular mechanisms involved in fibroblast-mediated tissue contraction is essential for developing future therapeutics for anti-scaring and fibrosis treatment not only for eyes, but also for a wide range of fibrotic diseases. The small Rho GTPase Rac1 is a master regulator of actin dynamics, which plays an essential role in protrusive activity, tissue repair and wound healing. A genome wide microarray study was performed with/without the transient treatment of human conjunctival fibroblasts with Rac1 inhibitor NSC23766 in a collagen gel contraction model to unveil the signalling events underlying contractile activity and the contribution of Rac1 activation. Through a comprehensive analysis that combined a pilot parallel study of scarring in an in vivo model in rabbit following glaucoma filtration surgery, and previously obtained microarray data of human ocular fibrotic diseases (including trachoma and thyroid-associated orbitopathy), it was identified that the contraction process consisted of two phases: an early phase that exhibited a classic serum/wound response profile with upregulation of genes related to inflammation, matrix remodelling, and transcription activation; and a late stage when the hyperactive signal receded and the gene profile progressed to promote fibrosis. The transient treatment with NSC23766 altered gene expression, and the early inhibition of Rac1 blocked the fibroblasts from entering the contractile phenotype as a whole. Interestingly, NSC23766 did not supress the mRNA expression of Matrix Metalloproteinase (MMP) 1, 3 and 10 during contraction, but reduced their enzymatic activity. The link between the activation of the Rho GTPase and MMP expression was subsequently investigated using MMP1 as an example. The results showed Rac1, Cdc42 and RhoA differently regulated MMP1 expression and secretion in fibroblasts during contraction, suggesting that the rate-limiting step for 3 modulating MMP is the release in the extracellular medium rather than expression levels, drawing some interesting new prospects for therapies. 4 Acknowledgments I would like to thank both of my primary and secondary supervisors, Dr. Maryse Bailly and Prof. Sir. Peng T. Khaw, for providing ultimate support, guidance, and mentoring throughout my PhD. Many thanks to Lady Peggy Khaw who very kindly provided help and guidance. I much appreciate Dr. Victoria Tovell’s contribution to the samples preparation work for the human conjunctival fibroblasts microarray. My thanks to Dr. David Simpson (Queen's University Belfast) for advice on techniques to analyse the microarray data. Thanks to Dr. Daniel Paull who performed the in vivo microarray and Dr. Jian-Liang Li (Sanford Burnham Prebys Medical Discovery Institute) who analysed the in vivo data. Many thanks to Ms. Diana Sefic-Svara who helped me a lot with the microscopy work. Thanks to Dr. Y. Itoh (University of Oxford) who kindly provided the in-house produced anti-MMP1 antibody. Thanks to Prof. Gregg B. Fields (Florida Atlantic University) who kindly provided the full-length MMP1 vector. Thanks to all of my group members (past and current) including Dr. Caroline Fittchet, Ms. Kasia Kozdon, Dr. Cynthia Yu-Wai-Man and Dr. Y-Hui Yang for the general support and help kindly provided. I would especially like to thank Dr. Zanetta Kechagia and Dr. Garima Sharma--without your company, those late nights and weekends in the lab would have been so long and lonely. Thanks to my parents, without whose love and support I would not be able to do anything. Thanks to Jun who is so supportive to my work and life. 5 Table of Contents Declaration ................................................................................................................ 2 Abstract ..................................................................................................................... 3 Acknowledgments ..................................................................................................... 5 Abbreviations ........................................................................................................... 11 List of Figures .......................................................................................................... 13 List of Tables ........................................................................................................... 18 Chapter 1 Introduction .......................................................................................... 21 1.1 Wound healing ............................................................................................... 21 1.1.1 Blood clotting and inflammation .............................................................. 21 1.1.2 Tissue growth (Proliferation) ................................................................... 22 1.1.3 Tissue remodelling (maturation) .............................................................. 24 1.2 Fibrosis and scarring...................................................................................... 25 1.2.1 Molecular mechanisms of fibrosis ........................................................... 26 1.2.2 Ocular Scarring ....................................................................................... 33 1.3 Fibroblast-mediated contraction..................................................................... 37 1.3.1 Fibroblasts ............................................................................................... 37 1.3.2 Cell-mediated contraction........................................................................ 38 1.3.3 Matrix degradation .................................................................................. 42 1.4 Small Rho GTPases ...................................................................................... 48 1.4.1 Small Rho GTPases and their regulators ................................................ 48 1.4.2 Rac1, Cdc42 and RhoA .......................................................................... 51 6 1.5 Aims and objectives ....................................................................................... 55 Chapter 2 Material and methods .......................................................................... 56 2.1 Fibroblast cell culture ..................................................................................... 56 2.1.1 Human conjunctival samples................................................................... 56 2.1.2 Cell culture .............................................................................................. 57 2.2 Collagen contraction assay ............................................................................ 57 2.2.1 Contraction assay with inhibitors ............................................................. 58 2.2.2 Cell viability assay ................................................................................... 59 2.3 Real-time PCR ............................................................................................... 59 2.3.1 RNA isolation .......................................................................................... 59 2.3.2 Reverse transcription .............................................................................. 60 2.3.3 qPCR ....................................................................................................... 60 2.4 Microarrays .................................................................................................... 62 2.4.1 The in vitro microarray............................................................................. 62 2.4.2 The in vivo microarray ............................................................................. 63 2.5 MMP activity assay ........................................................................................ 64 2.6 MMP1 ELISA ................................................................................................. 64 2.7 siRNA ............................................................................................................. 65 2.8 Protein extraction ........................................................................................... 66 2.8.1 Protein extraction from 2D culture ........................................................... 66 2.8.2 Protein extraction from 3D culture ........................................................... 67 2.9 Western blotting ............................................................................................. 67 2.10 Subcellular fractionation .............................................................................. 69 7 2.11 Cell staining and microscopy ....................................................................... 70 2.11.1 2D fluorescent imaging ......................................................................... 70 2.11.2 Collagen gel imaging ............................................................................. 71 2.12 Statistical analysis ......................................................................................
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