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Enhancing Cardiomyocyte Survival from Myocardial Infarction with Cardiac Stromal Cell-Secreted Factors

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Enhancing Cardiomyocyte Survival from Myocardial Infarction with Cardiac Stromal Cell-Secreted Factors Enhancing cardiomyocyte survival from myocardial infarction with cardiac stromal cell-secreted factors Chrystalla Constantinou A thesis submitted for the degree of Doctor of Philosophy and the Diploma of Imperial College National Heart and Lung Institute Faculty of Medicine Imperial College London 1 Declaration of originality I certify that this thesis, and the research to which it refers, are the product of my own work, conducted over the past four years as part of my PhD degree at Imperial College London. Any ideas or quotations from the work of other people puBlished or otherwise, or from my own previous work are fully acknowledged in accordance with the standard referencing practices of the discipline. 2 Acknowledgments First, I would like to express my sincere gratitude to National Heart and Lung foundation for my stipend throughout this project as well as my supervisors, Prof Michael Schneider and Dr Michela Noseda for their continuous support and excellent guidance. I would also like to thank the British Heart Foundation and the Wellcome Trust Foundation for supporting work of my laB, including this project. Besides my supervisors and sponsors, I would also like to thank the two examiners that have read my thesis and provided invaluaBle feedBack; Dr Nicola Smart and Dr Graeme Birdsey. Many thanks to the wider Imperial College community and all collaBorators, internal and external, that have contriButed to this work. I would also like to extend my gratitude to all members of Schneider and Noseda laBs, past and present, for all the useful discussions, lunch Breaks, coffee Breaks and mind- opening chats; special thanks to Patricia, Pelin, Antonio, Riccardo, Sam, Sara, Kevin and Liliana for not only Being my colleagues But also my friends. Special thanks to all my friends in London and Cyprus – especially Myria, Eleftheria, Elena, Christina, Gianna, Ioanna, Nicoletta, Nandia, Irene and Chara, thanks for Being the highlight of my days and Being there for me throughout this journey. Last But not least, to Marcos, there are oBviously no words to contain the amount of help and motivation I have received from you, the countless times you made me smile, please know that I will Be forever grateful. To my family Back home, mama, papa, Nicola and Marie, thanks for Being there to distract me when I needed it the most; I would not have made it without your constant support. And finally, my one and only Andrés, thank you for Being my Beam of light and reminding me what really matters in life. 3 Copyright Declaration The copyright of this thesis rests with the author. Unless otherwise indicated, its contents are licensed under a Creative Commons AttriBution-Non Commercial 4.0 International Licence (CC BY-NC). Under this licence, you may copy and redistriBute the material in any medium or format. You may also create and distriBute modified versions of the work. This is on the condition that: you credit the author and do not use it, or any derivative works, for a commercial purpose. When reusing or sharing this work, ensure you make the licence terms clear to others By naming the licence and linking to the licence text. Where a work has Been adapted, you should indicate that the work has Been changed and descriBe those changes. Please seek permission from the copyright holder for uses of this work that are not included in this licence or permitted under UK Copyright Law. 4 Abstract Myocardial infarction is the leading cause of death gloBally, and progression to heart failure is directly proportional to infarct size. Targeting cardiomyocyte loss is vital to stop cardiac damage. Previous data from our group show that intramyocardial injection of cardiac stromal cells (CSC) at time of infarct results in scar size reduction and improvement in ejection fraction. However, injected CSC are poorly retained, hence early paracrine signals might explain the oBserved improvement of cardiac function. Here we showed that injecting CSC-conditioned media into the mouse infarct Border zone reduced apoptotic cardiomyocytes >70% locally. SuBsequently, the paracrine effects of CSC were investigated, using human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) as a target more relevant to translation. In co-culture and conditioned medium studies, the CSC secretome markedly inhiBited human myocyte death, induced By three different cardiotoxic molecules; menadione, doxoruBicin and imatiniB. Follow-on studies were chiefly performed with menadione, showing preserved mitochondrial membrane depolarization and inhiBited ROS generation in the presence of CSC-conditioned media. Functional assays revealed that calcium cycling and action potential generation were also preserved following CSC- conditioned medium treatment of menadione-stressed cells. Characterization studies on the protective secretome pointed to exosome-independent molecules, which were thermolaBile and > 3 kDa in size. RNA-sequencing revealed that the CSC-secretome downregulated pro-apoptotic genes and preserved cardiac function and contractility markers in stressed hPSC-CM. A novel Bioinformatic tool was used to predict the potential ligand-receptor interactions under conditions of cardiomyocyte stress. In terms of proteomics, cytokine arrays highlighted protein factors enriched in conditioned media from protective versus non-protective populations. Human CSC were also characterized and found to resemble mouse CSC in molecular signature, as well as in their paracrine protective aBility. Thus, hPSC-CM provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, corroBorating human cardioprotection By the CSC-secretome and supporting the further investigation of CSC-conditioned medium as a potential cell-free therapeutic product. 5 Table of Contents Declaration of originality .............................................................................................. 2 Copyright Declaration .................................................................................................. 4 Abstract ....................................................................................................................... 5 Table of Contents ........................................................................................................ 6 List of Figures ............................................................................................................ 11 List of TaBles ............................................................................................................. 13 List of aBBreviations .................................................................................................. 14 1. Introduction ......................................................................................................... 20 The Burden of cardiovascular disease ......................................................... 20 Myocardial infarction and progression to heart failure ................................. 21 Oxidative stress in myocardial infarction ...................................................... 22 1.3.1. Menadione as an inducer of oxidative stress ........................................ 24 Cardiotoxic anti-cancer agents as sources of oxidative stress in the heart . 26 1.4.1. Anthracyclines like doxoruBicin ............................................................. 26 1.4.2. Tyrosine Kinase InhiBitors ..................................................................... 28 Mechanisms of cell death and implications for heart disease ...................... 30 1.5.1. A historical perspective of regulated cell death ..................................... 31 1.5.2. Death receptor pathway ........................................................................ 40 1.5.3. Mitochondrial pathway ........................................................................... 44 1.5.4. Cell death during myocardial infarction and heart failure ...................... 50 The regenerative capacity of the adult human heart .................................... 53 1.6.1. The promise of regenerative medicine in the heart ............................... 54 1.6.2. First-generation cell therapy for heart regeneration .............................. 55 1.6.3. Second-generation cell therapy for heart regeneration ......................... 59 Cardiac stem/progenitor cells ...................................................................... 60 1.7.1. The c-kit+ cardiac progenitor ................................................................. 60 1.7.2. The Sca-1+ cardiac progenitor ............................................................... 62 1.7.3. PDGFRα+ Cardiac Stromal Cells (CSC) ................................................ 65 Cell enhancement and cell-free approaches: the next generation? ............. 69 1.8.1. Growth factors ....................................................................................... 71 1.8.2. Cytokines and chemokines ................................................................... 82 1.8.3. Antioxidants ........................................................................................... 90 6 1.8.4. Paracrine-secreted hormones with newly discovered cardioprotective activities .............................................................................................................. 92 1.8.5. Mitochondrial transfer ............................................................................ 94 1.8.6. Other factors and small molecules .......................................................
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