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Final Copy 2019 01 23 Hampton-O'neil L Phd This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Hampton-O'Neil, Lea Title: Investigating the formation of erythroblastic islands General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. INVESTIGATING THE FORMATION OF ERYTHROBLASTIC ISLANDS Lea Alice Hampton-O’Neil University of Bristol School of Biochemistry University Walk Bristol UK January 2019 A dissertation submitted to the University of Bristol in accordance with the requirements of the degree of Doctor of Philosophy in the Faculty of Biomedical Sciences Word count: 42 001 i Abstract Erythropoiesis is one of the most efficient cellular processes in the human body producing approximately 2.5 million red blood cells every second. In humans, this process occurs in the bone marrow on a highly specialised niche called the erythroblastic island. This niche is comprised of a central macrophage surrounded by developing erythroblasts. The central macrophage is known to play an important role in erythropoiesis, but it is unknown how the differentiating erythroblast is initially attracted to the macrophage to form an island. The Eph receptor family is involved in contact inhibition of locomotion which controls how cells react when they initially encounter other cells, leading to adhesion or repulsion. We set out to explore the importance of the Eph receptor family in erythroblastic island formation. The first objective of this project was to create an assay and imaging pipeline to study the initial contact between macrophages and erythroblasts. Image analysis demonstrated we can observe long-lasting interactions as the macrophages bind one or more erythroblasts. Once this was sucessfully completed, this methodology was used to dissect the contribution different receptors made at the surface of the two cell types to island formation. We confirmed that human VCAM1+ and VCAM- bone marrow macrophages, and in vitro cultured macrophages are ephrin-B2 positive, whereas differentiating human erythroblasts express EphB4, EphB6 and EphA4. Furthermore, we detected a rise in integrin activation on erythroblasts at the stage at which the cells would bind, which is independent of Eph receptor presence. The application of a specific active integrin inhibitory peptide disrupted island formation illustrating the known importance of integrins. We next showed that specific inhibitory peptides or shRNA depletion of EphB4 also cause a significant reduction in the ability of macrophages to interact with erythroblasts. Bone marrow macrophages were also affected by EphB6 depletion illustrating a subtle difference between macrophage type. This study demonstrates for the first time that EphB expression on erythroblasts, independently from integrins, facilitates the initial recognition and subsequent interaction with macrophages. To conclude, we have developed methodology and imaging analysis which enables us to dissect the different roles surface receptors might play within erythroblastic islands. We have shown that EphB receptors and active integrin β1 are important for the recognition of the two cell types as binding partners, and their presence ensures that if one is lost, some contacts can still occur. This methodology can be used to decorticate the different pathways involved in the formation and function of erythroblastic islands in humans. This understanding could lead to a better yield and quality of erythropoiesis conducted in vitro. ii Acknowledgment I wish I had started writing these at the beginning of my PhD because there were so many people who have been there for me over the years and I don’t want to forget anyone. It takes a village to get a PhD. The first and most important thanks goes to Ash Toye. There are not enough words to explain how grateful I am to have had you as my supervisor. Your enthusiasm and understanding have kept me going these last 3 years. When I couldn’t see the big picture anymore, you were always able to help me dream again. Thank you from the bottom of my heart. The great people of A100 deserve so many thanks. I like to think that no one has more fun than us. I particularly want to thank Tim Satchwell and Marjolein Meinders. You guys have been there for me throughout, reassuring me and making me realise when 8 cells didn’t count as a result. I have grown as a scientist and as a person from knowing you guys. Tim, you have been the best and most fun person to sit next to in the office and you always made things feel less world shattering than they were. Thank you! Thank you MJ for being such a good friend throughout. You have seen me cry, you have seen me eat, you have seen me celebrate, you’ve been there for it all. May there always be Swoon days in the future. Nat Di Bartolo, you are the nicest person and I am so glad you were there for all the fun, I hope it will continue. Steph Pellegrin you are the most generous person I know. You were there from the beginning of my project and you were always there when I had a question, even if you were in the middle of something. Joe Hawksworth, you have listened to me moan so much without ever flinching. Thank you (and thank you for always having a great story). Pedro Moura, thank you for all the lively debates about food and every topic under the sun. Beth Hawley, thank you for making me be more sporty than I actually am! I never thought I could have run a 10k mud run before you. Katy Haydn Smith, thank you for your cheerfulness and making a 3 hour delay at an airport a lot more fun! Charlie Severn, thank you for taking the time to read the paper so many times. I truly appreciate that. iii I have to thank the amazing facilities team at the University. Their help, enthusiasm and cheerfulness always brought joy when working with them. To name a few: Andrew Herman, Lorena Sueiro Ballesteros, Stephen Cross, Katie Jepsen… I want to thank all my Bristol friends. You have all been amazing. The amazing Wellcome Trust 5: Melanie Panagi, Amy Dey, Rob Lees, Sonam Gurung. From Day 1, it’s been love at first sight. We’ve seen it all, the good, the bad, the ugly. I am so glad the Wellcome Trust brought us together. My housemates over the years: Amy Dey, Helen Hoogewerf-McComb, Sonam Gurung, Maria Gomez, Alex Fletcher-Jones and Rachel Humphries. Thank you for all being you. It has been 3 great years made more special by getting to come home to you guys. Helen you get a special mention for having been there for me for the last 8 years. I wouldn’t have this PhD without you. More than anyone, you know how difficult believing in myself is for me. Your encouragements throughout the years and your ability to always make me laugh are invaluable to me. I know things haven’t always been easy but you definitely have made getting through 8 years of Uni better. I also need to thank my Union friends without whom the world would definitely not be as fun or adventurous: Laura Ho, Jamie Cross, Lauren Canvin, Kitty Flint, Letty Key…. To Steph Wiedemann, Davina Chao and Grace Vance. We are the Cliquest Flickest and the last 4 years have been great with you guys. You helped me stay an undergrad throughout my postgrad. That is one of the best gifts a girl can get. I would be remiss if I didn’t include my parents who are some of the most supportive and amazing parents I know. They always want the best for me and I love them so much. Thank you for loving me too and supporting me throughout. Finally, I want to thank my examiners for taking the time to read this thesis. I hope you found it as interesting as I found these last three years. iv Declaration I declare that the work in this dissertation was carried out in accordance with the requirements of the University's Regulations and Code of Practice for Research Degree Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, the work is the candidate's own work. Work done in collaboration with, or with the assistance of, others, is indicated as such. Any views expressed in the dissertation are those of the author. SIGNED: ............................................... DATE:.......................... v Table of Contents 1 Chapter 1 – Introduction ........................................................................ 1 Hematopoietic Stem Cells ................................................................................. 1 Erythropoiesis .................................................................................................... 4 A multi-stage process ................................................................................. 4 Bone marrow macrophages and egress ...................................................
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