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Histamine Is the Macrophage-Derived Factor That Plays a Crucial Role In Histamine is the Macrophage-derived factor that plays a crucial role in promoting Axon Regeneration of Retinal Explants By Khyati Walia A thesis submitted in conformity with the requirements for the degree of MSc. Department of Physiology University of Toronto 2020 Histamine is the Macrophage-derived factor that plays a crucial role in promoting Axon Regeneration of Retinal Explants Khyati Walia Master of Science Department of Physiology University of Toronto 2020 Abstract The role of macrophages in promoting axon regeneration in the injured mammalian CNS is still strongly debated. While there have been past studies that reported regenerative effects induced by inflammation following injuries to the lens or the optic nerve, there are still several gaps in our understanding of the underlying mechanisms behind achieving that successful axon regeneration. With the use of three different primary cell lines, we show that histamine is the active macrophage-derived factor that is responsible for neurite growth- promoting effects observed in the retinal explant cultures. We also report that histamine is mediating these effects by binding to the H1 receptors found on the astroglial cells. Furthermore, our findings indicate that histamine is influencing the exosome secretion from astroglial cells in eliciting these effects. Therefore, our results address the role of macrophages and show the mechanism whereby they are promoting the axon regrowth at the CNS injury site. ii Acknowledgements First and foremost, I would like to express my deepest gratitude to my supervisor Dr. Monnier for making me a part of his team and for giving me the opportunity to carry out this project. I would also like to thank my committee members, Dr. Zhong Ping Feng and Dr. Koeberle for providing their feedback on my progress during the committee meetings. I would also like to specifically thank Nahal Farhani and Amy from Dr. Wrana’s lab for training me on specific lab techniques. My sincere thanks go to the entire team of Dr. Wrana for allowing me to use their Zetaview Particle Meter and for helping with the mRNA Sequencing analysis. I would also like to extend my gratitude to Hidekiyo Harada for helping with the mRNA Sequencing. Besides, I am grateful to all my teammates for providing me with such a positive atmosphere in these past couple years. Lastly, I would like to thank my parents, my brother and my partner for being that major support system for me throughout this time. Without you, I never would have even imagined coming this far. It was your love and encouragement that allowed me to stay committed. I would also like to thank my mentor, Dr. Krepinsky. If it was not for your advice, I may not even have pursued graduate studies. I would also like to sincerely thank Vision Science Research Program for supporting this project. iii Table of Contents Abstract………………………………………………………………………………………ii Acknowledgements………………………………………………………………………….iii List of Figures …...………………………………………………………………………....vii List of Tables ……..…………………………………………………………………………ix List of Abbreviations ……………………………………………………………………......x Chapter 1: Introduction……………………………………………………………………..1 1.1 Injury to the Central Nervous System …………………………………………………1 1.2 Astrocytes in CNS Injury and Repair…………………………………………………..1 Astrocytes and their normal physiological functions………………………………..........1 Glial scar formation……………………………………………………………………….4 1.3 Exosomes and Axon Regeneration…………………………………………………….10 1.4 The role of Immune System in CNS Injury…………………………………………..14 1.5 Earlier Studies on CNS Recovery……………………………………………………..16 1.6 Role of Macrophages in CNS Injury…………………………………………………..17 Physiological and Pathological functions of CNS Macrophages and Microglia………..17 M1 vs. M2 phenotype……………………………………………………………………20 1.7 Role of Histamine in Neuroinflammation…………………………………………….23 Histamine synthesis and physiological function…………………………………….......23 Histamine receptors and their expression………………………………………………..23 Effect of Histamine on Astrocyte function………………………………………………27 1.8 Rationale………………………………………………………………………………..31 Studies showing regenerative effects of Macrophages in Lens Injury or ONC model….31 Studies arguing against the involvement of Oncomodulin or Activated Macrophages in Axonal Regeneration……………………………………………………………………36 1.9 Hypothesis and Aims…………………………………………………………………..40 2 Chapter 2: Material and Methods……………………………………………………43 2.1 Isolation and Plating of Mixed Cortical cells…………………………………………....43 2.2 Obtaining an Enriched Astrocytes culture……………………………………………….45 2.3 Purification of Exosomes by Differential Ultracentrifugation..........................................46 2.4 Quantification of Exosomes using ZETAVIEW Particle Meter………………………...46 2.5 Isolation of Peritoneal Macrophages…………………………………………………….49 2.6 Histamine H1 Receptor Knockout Animals……………………………………………..50 2.7 Cell Culture treatments…………………………………………………………………..50 2.8 Chick Retinal Explant Outgrowth Assay………………………………………………...51 2.9 Immunocytochemistry………………………………………………………………...…52 iv 2.10 mRNA Sequencing…………………………………………………………………..53 2.11 Statement of Ethics for Animal Use…………………………………………………54 2.12 Microscopy…………………………………………………………………………..54 2.13 Statistical Analysis…………………………………………………………………...54 Chapter 3: Results………………………………………………………………………….55 Aim I: Role of Macrophages in promoting neurite outgrowth of Retinal Explants........55 3.1 Neurite outgrowth is promoted with the treatment of Macrophages Conditioned Media 3.2 Neurite growth promoting effects induced by Macrophages are dependent on glial cells 3.3 Activated Macrophages promote neurite outgrowth of Retinal Explants when cultured on Astrocytes Aim II: Histamine is the Activated Macrophage-derived factor that is promoting neurite length………………………………………………………………………………64 3.4 Inhibiting histamine production inhibits neurite growth promoting effects of Activated Macrophages.. 3.5 Histamine treatment promotes neurite outgrowth of retinal explants.. Aim III: Histamine’s neurite growth promoting effects are mediated by its binding to H1 receptor…………………………………………………………………………………70 3.6 Treatment with H1 receptor agonist promotes neurite outgrowth of retinal explants.. 3.7 Histamine H1 Receptor Knockout Mice-derived astrocytes show decrease in the neurite outgrowth.. Aim IV: Exosomes are involved in mediating the neurite growth promoting effects….79 3.8 Differential gene expression analysis show H1-antagonist treatment results in downregulation of gene involved with exosome release 3.9 H1-agonist treatment promotes exosome secretion 3.10 inhibiting exosome secretion decreases neurite outgrowth.. Aim V: Astrocyte-derived exosomes promote neurite outgrowth both on Laminin and CSPG……………………………………………………………………………………….88 3.11 Astrocyte-derived exosomes treatment increases growth on Laminin.. 3.12 Astrocyte-derived exosomes treatment increases growth even on CSPG.. Aim VI: Astrocyte-derived exosomes promote neurite outgrowth via Wnt signaling pathway…………………………………………………………………………………....91 3.13 Blocking Wnt secretion decreases exosome-induced neurite growth promoting effects on Laminin… v 3.14 Blocking Wnt secretion decreases exosome-induced neurite growth promoting effects even on CSPG Chapter 4: Discussion (& Future Directions)..………………………………………….94 Chapter 5: Conclusion…………………………………………………………………...101 Chapter 6: Appendix…………………………………………………………………….102 Chapter 7: Bibliography…………………………………………………………………105 vi List of Figures Figure 1-1. A schematic representation demonstrating astrocytes play an important role in supporting neurons in the CNS………………………………………………………………..3 Figure 1-2. Schematic (A) and photomicrograph (B & C) of a Spinal Cord Injury lesion showing the discrete tissue compartments ………………………………………………….5 Figure 1-3. Schematic representation of M1 and M2 polarization of macrophages…….......20 Figure 1-4. Schematic representation of classical binding sites of histamine and the sequential signaling pathways that are activated on H1, H2, H3 or H4 receptor binding…...24 Figure 2-1. Zetaview Nanoparticle Tracking Analyzer …………………………………….46 Figure 3-1. Neurite outgrowth is promoted with treatment of Activated MCM……………57 Figure 3-2. The neurite growth promoting effects induced by Activated MCM treatment are dependent on the glial cells………………………………………………………………….60 Figure 3-3. Activated MCM promotes neurite outgrowth when retinal explants are cultured on just astrocytes…………………………………………………………………………….62 Figure 3-4. Blocking Histamine production inhibits the neurite growth promoting effects...65 Figure 3-5. Histamine treatment promotes neurite outgrowth of the retinal explants………68 Figure 3-6. Histamine H1 agonist treatment promotes neurite outgrowth of retinal explants cultured on non-activated astrocytes………………………………………………………...72 Figure 3-7. Histamine H1 agonist treatment promotes neurite outgrowth of retinal explants cultured on activated astrocytes…………………………………………………………..….74 vii Figure 3-8. H1-KO astrocytes resulted in decreased neurite outgrowth…………………….77 Figure 3-9. H1-agonist treatment increases exosome secretion…………………………….82 Figure 3-10. GW4869 treatment decreases exosome secretion……………………………..84 Figure 3-11. Inhibiting exosome secretion decreases neurite outgrowth…………………..86 Figure 3-12. Astrocyte-derived exosomes promote neurite outgrowth…………………….89 Figure 3-13. Astrocyte-derived exosomes promote neurite outgrowth despite the presence of CSPG………………………………………………………………………………………..90 Figure 3-14. IWP2 treatment decreases the exosome-induced neurite growth…………….92 Figure 3-15. IWP2 treatment decreases the exosome-induced
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