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Rejuvenation of Aged Heart Explant-Derived Cells for Repair of Ischemic Cardiomyopathy

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Rejuvenation of Aged Heart Explant-Derived Cells for Repair of Ischemic Cardiomyopathy Rejuvenation of Aged Heart Explant-Derived Cells for Repair of Ischemic Cardiomyopathy Ghazaleh Rafatian This thesis is submitted to the Faculty of Graduate and Postdoctoral Studies as partial fulfillment of the Doctor of Philosophy program in Cellular Molecular Medicine. Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa, Ottawa, ON Supervisors: Darryl R Davis, MD Erik J Suuronen, PhD © Ghazaleh Rafatian, Ottawa, Canada, 2019 Table of Contents Sources of Funding................................................................................................................. VIII Abstract ..................................................................................................................................... IX List of Tables .............................................................................................................................. X List of Figures ........................................................................................................................... XI List of abbreviations ............................................................................................................... XIII Acknowledgments ................................................................................................................. XVII 1. INTRODUCTION ................................................................................................................... 1 1.1.1 Aging .............................................................................................................................. 1 1.1.1.1 Genomic instability and telomere shortening .............................................................. 2 1.1.1.2 Oncogenic stress and oxidative stress ....................................................................... 5 1.1.1.3 Nutrient sensing ........................................................................................................... 6 1.1.1.4 Loss of protein homeostasis (proteostasis) .................................................................. 6 1.1.1.5 Epigenetic alterations .................................................................................................. 7 1.1.1.6 Cellular senescence...................................................................................................... 7 1.1.2 Cardiac aging ................................................................................................................ 10 1.1.3 Cardiomyocyte aging .............................................................................................. 12 1.2.1 Myocardial infarction ................................................................................................... 13 1.2.2 Myocardial infarction risk factors ........................................................................... 13 1.2.3 Myocardial infarction consequences ....................................................................... 14 1.2.4 Cellular changes during ischemia ........................................................................... 15 1.2.5 Myocardial healing after infarction ........................................................................ 16 II 1.2.6 Effects of age on endogenous responses to myocardial infarction ............................... 19 1.3.1 Cardiac regeneration ..................................................................................................... 20 1.3.2 Stem cells for cardiac dysfunction ................................................................................ 21 1.3.3 Cardiac stem cells ......................................................................................................... 23 1.3.4 Stem cell aging ............................................................................................................. 27 1.3.5 Stem cell and myocardial infarction ............................................................................. 29 1.4 Refining cardiac stem cells .............................................................................................. 30 1.4.1 Genetic modification .................................................................................................... 32 1.4.2 Biomaterials .................................................................................................................. 33 1.4.3 Other enhancement strategies ....................................................................................... 33 1.5 Mybl2 (Myb-Like Protein 2) ........................................................................................... 34 1.5.1 The role of Mybl2 in regulation of the cell cycle ......................................................... 36 1.5.2 Mybl2 role in senescence ............................................................................................. 39 2. STUDY RATIONALE, AIMS & HYPOTHESES ................................................................... 41 2.1 Rationale .......................................................................................................................... 41 2.2 Research Aims ................................................................................................................. 43 2.3 Hypotheses....................................................................................................................... 43 3. METHODS ............................................................................................................................... 45 3.1 Experimental animals. ..................................................................................................... 45 3.1.1 Generation of chronic ischemic model. ........................................................................ 45 3.1.2 Evaluation of cardiac function using echocardiography .............................................. 46 3.2 Explant-derived cardiac stem cell culture ....................................................................... 46 3.3 EDC cell count................................................................................................................. 47 3.4 Quantification of EDC proliferation ................................................................................ 47 III 3.5 Flow cytometry ................................................................................................................ 47 3.6 Cardiogenic culture conditions ........................................................................................ 48 3.6.1 Quantitative polymerase chain reaction (qPCR) evaluation of cardiac transcripts ...... 49 3.6.2 Flow cytometry evaluation of cardiac markers ............................................................ 49 3.7 Generation of conditioned media for angiogenesis, migration and paracrine profiling .. 49 3.7.1 Paracrine profiling of EDC conditioned media ............................................................ 50 3.7.2 Angiogenesis assay ....................................................................................................... 50 3.7.3 Migration assay............................................................................................................. 51 3.8 Characterization of extra-cellular vesicles secreted by EDCs ......................................... 52 3.9 Cellular senescence .......................................................................................................... 52 3.10 Evaluation of telomere length and telomerase system .................................................. 52 3.11 Reactive Oxygen species content .................................................................................. 54 3.12 Antioxidant reserves evaluation .................................................................................... 54 3.13 Microarray ..................................................................................................................... 55 3.14 Lentiviral vector production and transduction............................................................... 56 3.14.1 Plasmid constructs ...................................................................................................... 56 3.14.2 Transformation ........................................................................................................... 56 3.14.3 Viral packaging ........................................................................................................... 56 3.14.4 Virus titration and transduction .................................................................................. 57 3.15.1 Mybl2 plasmid validation and Backbone plasmid generation.................................... 57 3.15.2 Mybl2 over-expression ............................................................................................... 60 3.16 Rapamycin and bromoindirubin-3-oxime (BIO) cell treatment .................................... 60 3.17 In vivo testing................................................................................................................. 60 3.17.1 Functional evaluation ................................................................................................. 61 3.17.2 Histology .................................................................................................................... 61 IV 3.17.3 Retention ..................................................................................................................... 62 3.17.3.1 Measurement of long-term EDC retention by GFP-labeling................................... 62 3.17.3.2
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