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Idiopathic Pulmonary Fibrosis: Exploration of Aberrant Epithelial Wound Repair and Stem Cell-Mediated Regenerative Approaches

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Idiopathic Pulmonary Fibrosis: Exploration of Aberrant Epithelial Wound Repair and Stem Cell-Mediated Regenerative Approaches This work is protected by copyright and other intellectual property rights and duplication or sale of all or part is not permitted, except that material may be duplicated by you for research, private study, criticism/review or educational purposes. Electronic or print copies are for your own personal, non- commercial use and shall not be passed to any other individual. No quotation may be published without proper acknowledgement. For any other use, or to quote extensively from the work, permission must be obtained from the copyright holder/s. Idiopathic pulmonary fibrosis: exploration of aberrant epithelial wound repair and stem cell-mediated regenerative approaches Khondoker Mehedi Akram School of Postgraduate Medicine Institute for Science and Technology in Medicine Keele University Thesis submitted to the Keele University for the degree of Doctor of Philosophy February 2013 List of contents Abstract…………………………………………………………………………… II Acknowledgements……………………………………………………………….. IV Publications……………………………………………………………………….. VI Abbreviations……………………………………………………………………... VII Chapter contents…………………………………………………………………... XI List of figures……………………………………………………………………... XIX List of tables………………………………………………………………………. XXIII Dedication………………………………………………………………………… XXIV I Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal form of fibrotic lung disease. The pathogenesis of IPF is unclear. An aberrant alveolar epithelial wound repair is likely to be involved in the disease process. Alveolar bronchiolisation, a process where bronchiolar Clara cells migrate into the affected alveoli, is a manifestation of abnormal alveolar wound repair. The role of Clara cells during alveolar injury repair in IPF is controversial. This study was undertaken to investigate the role of Clara cells in alveolar epithelial wound repair and pulmonary fibrosis. Currently, there is no curative treatment for IPF; therefore, stem-cell mediated regenerative therapy has been suggested. In this study, the paracrine role hMSC and hESC on pulmonary epithelial wound repair has also been evaluated. A direct-contact co-culture in vitro model was utilised to evaluate the role of Clara cells on alveolar epithelial cell wound repair. Immunohistochemistry was conducted on IPF lung tissue samples to replicate the in vitro findings ex vivo. The paracrine role of hMSC and hESC on pulmonary epithelial cells was evaluated by utilising the in vitro wound repair system. This study demonstrates that Clara cells induce apoptosis in AEC through a TRAIL- dependent mechanism, resulting in significant inhibition of wound repair. Furthermore in the IPF lungs, TRAIL-expressing Clara cells were detected within the fibrotic alveoli, together with widespread AEC apoptosis. This study also demonstrates that hMSC enhance AEC and SAEC wound repair via a paracrine mechanism through stimulation of cell migration; whereas, secretory factors of differentiated hESC promote AEC wound repair through stimulation of both cell proliferation and migration. II Through this study I propose a novel hypothesis which implies that the extensive pro- fibrotic remodelling associated with IPF could be driven by TRAIL-expressing Clara cells inducing AEC apoptosis through a TRAIL-dependent mechanism. My study also supports the notion of clinical application of hMSC and hESC or their secretory products as regenerative therapeutic modality for IPF. III Acknowledgements First of all, I wish to acknowledge and thank to my lead supervisor Dr Nick R Forsyth and co-supervisor Prof. Monica Spiteri for their support that has undoubtedly helped me to become a self confident scientist. Without their guidance, suggestions and numerous revisions the completion of this thesis would not have been possible. I am truly grateful to them. I would also like to thank my advisor Dr Alan Richardson for his suggestion and all the supports that he has given me throughout my PhD course. I would like to thank to our previous Postdoc Dr Amiq Gazdhar for his help in the early days of my PhD research. My special thank to my colleague Ms Nicola Lomas with whom, collaboration has led to development of a novel hypothesis of this thesis and a fantastic publication. I also thank to my friendly colleague Dr Neil Patel for his encouragement throughout my thesis writing. I would like to thank Dr Heidi Fuller as well for performing mass spectrometry analysis on my samples. People of Skills Lab- my friends and colleagues have really made my long PhD research period enjoyable and less-stressful. My special thank to Deepak and Angeliki for providing me some reagents and antibodies for some of my experiments. I would also like to thank Hare for her effortless encouragement, Sammy for her amazing graphical ideas for my posters, Richard for his IT specialty that kept my laptop fast and „hang-free‟, Sohel for his help as a brother and Kiren for her „all time good wishes‟ for me. I also wish to give my cordial thank to Alex, Tina, Mike, Abbey, Jane, Vas, Hu Bin, Rupert, Ling, Feng, Param and Sanya; these people helped me in many ways. I would like to give a big thank to „good fella‟ Dr Ian Wimpenny for his helpful suggestions in preparation of my thesis. I am IV thankful to all people of Guy Hilton Research Centre, in particular, Steff and Anne who processed all of my purchase orders throughout my PhD. I would like to thank my parents who provided me the support and encouragement throughout my long academic career that has now reached to the completion stage of my PhD. There is no doubt that without their encouragement, I could not have reached the stage that I am now in; my heartfelt gratitude to them. I am grateful to my loving wife who never complained about my clock-less and weekend-less work schedules. Her support and encouragement pushed me towards a successful end of my thesis. I would like to say, “Thank you; one day I will pay you back for all of your sacrifice.” Finally, I would like to extend my gratitude to my funding bodies, Medical Research Council-Dorothy Hodgkin Postgraduate Award and Chest Fund charity from University Hospital of North Staffordshire. I am also thankful to God for keeping me mentally and physically sound to pursue the hardest research works and completion of my thesis. V Publications ■ Peer reviewed journals 1. Akram KM, Lomas NJ, Spiteri MA, Forsyth NR. “Clara cells inhibit alveolar epithelial wound repair via TRAIL-dependent apoptosis”. Eur Respir J. 2012 Jul 12. [Epub ahead of print]. Work from the Chapter 3. 2. Lomas NJ, Watts KL, Akram KM, Forsyth NR, Spiteri MA. “Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers”. Int J Clin Exp Pathol. 2012; 5(1) :58-71. [Epub 2012 Jan 7]. ■ Review/Book Chapters 1. Akram KM, Samad S, Spiteri M, Forsyth NR. ”Mesenchymal stem cell therapy and lung diseases”. Adv Biochem Eng Biotechnol. 2012 Jul 8. [Epub ahead of print]. Work from the Chapter 1. VI Abbreviations ACTC1 Actin, alpha, cardiac muscle 1 AEC Alveolar epithelial cell AECI Type I alveolar epithelial cell AECII Type II alveolar epithelial cell AFP Alpha-fetoprotein AFP α-Fetoprotein ALP Alkaline phosphatase ATCC American type culture collection BAL Bronchoalveolar lavage BASCs Bronchioloalveolar stem cells bFGF Basic fibroblast growth factor BMA Bone marrow aspirate CCSP Clara cell secretory protein CFU-F Colony forming unit- fibroblast COPD Chronic obstructive pulmonary disease CT Computed tomography CTGF Connective tissue growth factor ddH2O Double distilled water dH2O Distilled water DMEM Dulbeco‟s Modified Eagle Medium DMSO Dimethyl sulfoxide EB Embryoid body EBV Epstein-Barr-Virus VII ECM Extra cellular matrix EGF Epidermal growth factor EMT Epithelial-mesenchymal transition eNOS Endothelial nitric oxide synthase ESC Embryonic stem cells ET-1 Endothelin-1 FBS Foetal bovine serum FGF Fibroblast growth factor GAG Glycosaminoglycan GvHD Graft-versus-host disease hESC Human embryonic stem cells HGF Hepatocyte growth factor HHV Human herpesvirus hMSC Human mesenchymal stem cells HRCT High resolution computed tomography HSC Haematopoitic stem cell hTERT Human telomerase reverse transcriptase IGF Insulin growth factor IGF-1 Insulin-like growth factor-1 IGFBP-7 Insulin-like growth factor binding protein-7 IIP Idiopathic interstitial pneumonia IL Interleukin ILD Interstitial lung disease iNOS Inducible nitric oxide synthase IPF Idiopathic pulmonary fibrosis VIII KGF Keratinocyte growth factor KO-DMEM Knock out-Dulbeco‟s Modified Eagle Medium KO-SR Knock out-Serum replacement MEF-CM Mouse embryonic fibroblast-conditioned media MEFs Mouse embryonic fibroblast MMP Matrix metalloproteinase MSC Mesenchymal stem cells NO Nitric oxide Oct-4 Octamer-binding protein-4 OSF-2 Osteoblast specific factor-2 pAEpiC Primary alveolar epithelial cells PBS Phosphate-buffered saline PDGF Platelet-derived growth factor PET Polyethylene terephthalate PFA Paraformaldehyde PGE2 Prostaglandin-E2 proSP-C proSurfactant protein-C PSA Penicillin-Streptomycin-Amphotericin B ROS Reactive oxygen species RT Room temperature SABM Small airway basal media SAEC Small airway epithelial cells SAGM Small airway growth media SCID Severe combined immunodeficient SF-DMEM Serum-free DMEM IX SFTPC Surfactant protein-C SOX1 Sex determining region Y-box 1 SSEA-1 Stage-specific embryonic antigen-1 SSEA-4 Stage-specific embryonic antigen-4 TGF-β1 Transforming growth factor-β1 TIMP Tissue inhibitory metalloproteinase TNF-α Tumour necrosis factor-α TRAIL TNF-related apoptosis-inducing
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