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Engineering Biointerfaces to Reveal Collagen IV Disease Mechanisms Ngandu Mpoyi, Elie (2017) Engineering biointerfaces to reveal collagen IV disease mechanisms. PhD thesis. https://theses.gla.ac.uk/9032/ Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Engineering biointerfaces to reveal collagen IV disease mechanisms Elie Ngandu Mpoyi (BSc (Hons), MRes2) Submitted in fulfilment of the requirements for the Degree of Doctor of Philosophy Biomedical Engineering School of Engineering University of Glasgow August 2017 Abstract Basement Membranes (BMs) are specialised extracellular matrix (ECM) structures that underlie all endothelial and epithelial cells, and provide structural support to tissues as well as influence cell behaviour and signalling. Mutations in the BMs major component collagen IV cause eye, kidney and cerebrovascular disease including intracerebral haemorrhaging (ICH). Haemorrhagic stroke accounts for 15% adult stroke and 50% paediatric stroke, and carries the worst prognosis and there are no therapeutic strategies. Mutations in the genes COL4A1/COL4A2 (collagen IV alpha chain 1 and 2) cause BM defects due to mutant protein incorporation in the BM or its absence by ER retention, and ER-stress due to intracellular accumulation of collagen IV. Despite this, the mechanism(s) of collagen IV mutations disease remain poorly characterised. To provide novel insights into mechanisms of collagen diseases, this study investigates the effect of defined engineered biointerfaces on cell behaviour/signalling, collagen secretion in COL4A2 mutant and wild-type cells. Atomic force microscopy and spectroscopy were employed together with confocal and biochemical analyses of cells cultured on engineered synthetic polymers, poly(ethyl acrylate) and poly(methyl acrylate), coated with ECM proteins, namely laminin, collagen IV and fibronectin. This enabled us to address the hypothesis that biomaterials may alter the behaviour of COL4A2+/G702D mutant cells by overcoming some of the defects caused by the mutation and rescuing the downstream effect of the ER stress. Of the ECM proteins that were used, only fibronectin was observed to undergo a drastic structural change depending on the substrate chemistry. On poly(ethyl acrylate), fibronectin was assembled into fibrillary networks upon adsorption, and these nanonetworks induced increased secretion of Col4a2 in COL4A2+/G702D cells than on poly(methyl acrylate) or control glass. The behaviour of the mutant cells appeared to be influenced by the underlying biointerface, increased levels of molecular chaperones and reduced ER area suggested an increased collagen IV folding capacity when the cells were cultured on the FN nanonetworks compared to the other surfaces. COL4A2+/G702D cells interacted with the adsorbed proteins and were able to mechanically translocate them. Enhanced formation of focal adhesions was also seen on FN-coated polymers, where ligand density and actin-myosin contractility accounted for the observed increase in cell adhesion strength. The stiffness of the mutant fibroblasts and of their ECMs was found to be 10 times lower than that of the wild-type cells; interestingly, mutant cells cultured on FN nanonetworks on poly(ethyl acrylate) were able 1 to deposit a protein matrix with significantly higher Young modulus than on glass or poly(methyl acrylate). These findings suggest that biomaterials are able to influence the behaviour of these mutant cells through changes in the interfacial layer of adsorbed proteins presented to them. Collectively, these data provide an understanding of the effect of mutations on cell characteristic and a basis of concept that material may be employed to modulate effects of mutations of collagen/ECM molecules. Understanding the mechanisms through which these surfaces trigger a change in cell response will prove valuable for the development of new therapeutic approaches to address pathologies due to collagen IV mutations. In this respect, further investigation is needed to dissect the signalling pathways involved. 2 Table of Contents List of Tables ……………………………………………………………………………...7 List of Figures …………………………………………………………………………..…8 Acknowledgement ………………………………………………………………………...11 Author Declaration ………………………………………………………………………..12 Presentations and Publications ……………………………………………………………13 Definitions / Abbreviations ……………………………………………………………….14 Chapter 1 General Introduction 1. 1 Extracellular Matrix ..................................................................................................... 18 1. 2 Fibronectin ................................................................................................................... 19 1. 3 Basement Membranes .................................................................................................. 20 1. 3. 1 Function of the BM ............................................................................................... 21 1. 3. 2 Composition, structure and assembly of BMs ....................................................... 23 1. 3. 2. 1 Laminin .......................................................................................................... 24 1. 3. 2. 2 Perlecan .......................................................................................................... 25 1. 3. 2. 3 Nidogen .......................................................................................................... 26 1. 3. 2. 4 Collagen ............................................................................................................. 27 1. 3. 2. 5 Collagen IV .................................................................................................... 31 1. 3. 2. 6 Diseases to collagen IV mutations ................................................................. 35 1. 3. 2. 7 Mechanisms of collagen IV mutations .......................................................... 38 1. 4. Biointerfaces ............................................................................................................... 40 1. 4. 1 Cell interaction with biomaterials ......................................................................... 41 1. 5 Work leading to project ................................................................................................ 46 1. 6 Project Aims ................................................................................................................. 48 Chapter 2 Materials and Methods 2. 1 Reagents and Solutions ................................................................................................. 51 2. 2 Surface preparation ....................................................................................................... 51 2. 3 Protein adsorption ......................................................................................................... 51 2. 4 Quantification of adsorbed protein................................................................................ 51 3 2. 5 Immunostaining of adsorbed protein ............................................................................ 52 2. 6 Water contact angle ....................................................................................................... 52 2. 7 Atomic force microscopy .............................................................................................. 53 2. 8 Calculus of the fractal dimension .................................................................................. 53 2. 9 Cell Culture ................................................................................................................... 54 2. 10 Cell proliferation analysis ........................................................................................... 55 2. 11 Cell attachment assay .................................................................................................. 55 2. 12 Early Adhesion Assay ................................................................................................. 55 2. 13 Cell adhesion strength measurements ......................................................................... 56 2. 14 Extracellular matrix analysis ....................................................................................... 58 2. 14. 1 Immunofluorescence to quantification secretes matrix........................................ 58 2. 14. 2 ELISA assay for secreted collagen ...................................................................... 59 2. 14. 3 In-cell Western assay ........................................................................................... 60 2. 14. 4 Passaging of mutant cells from FN-coated interfaces to glass ............................. 60 2. 14. 5 ER stress analysis in primary dermal fibroblasts ................................................. 60 2. 15 ERK1/2 phosphorylation ............................................................................................. 61 2. 16 Matrix reorganisation and formation .........................................................................
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