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Characterizing Retinal Stem Cell Proliferation and Differentiation Potentials

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Characterizing Retinal Stem Cell Proliferation and Differentiation Potentials Characterizing Retinal Stem Cell Proliferation and Differentiation Potentials by Kenneth N. Grisé A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Molecular Genetics University of Toronto © Copyright by Kenneth N. Grisé 2021 Characterizing Retinal Stem Cell Proliferation and Differentiation Potentials Kenneth N. Grisé Doctor of Philosophy Department of Molecular Genetics University of Toronto 2021 Abstract A quiescent population of retinal stem cells (RSCs) in the adult mammalian eye retains the ability to proliferate and generate all retinal cell types when cultured in vitro. Thus, understanding the biological mechanisms that regulate RSC quiescence, proliferation and differentiation could lead to new possibilities for retinal endogenous repair or cell therapy. Previous in vitro experiments in our lab have implicated two proteins, BMP and sFRP2, as potential mediators of RSC quiescence. Herein, I show that antagonism of BMP or sFRP2 proteins in the adult eye can induce the proliferation and expansion of RSCs in vivo and potentiate the effects of exogenous growth factors. Using genetic lineage tracing, I found that RSCs express the gene Msx1. Moreover, in response to BMP/sFRP2 antagonism with growth factor stimulation, photoreceptor degeneration, or all combined, Msx1-lineage cells migrate from the RSC niche into the retina and express markers of mature retinal neurons, including photoreceptors. To identify novel regulators of RSC proliferation, I developed a phenotypic drug screening platform and tested a library of small molecules with well-characterized molecular targets. Screening identified synthetic glucocorticoid (GC) agonists as compounds that increase RSC ii self-renewal and retinal stem and progenitor cell (RSPC) proliferation. GC agonists did not affect the differentiation profile of RSPCs, suggesting proliferation and differentiation are dissociable processes. In addition, injection of GC agonist, dexamethasone, into the adult mouse eye resulted in proliferation in the RSC niche. Intrinsic and extrinsic signals can influence RSPC fate specification. Here we used a multifunctional antagonist of TGFβ, BMP and Wnt signaling – COCO -- to direct RSC progenitors to produce up to 100% cone photoreceptor progeny. Transcriptome profiling of endogenous cones and RSC-derived cones showed that both cell types are genetically similar and distinct from undifferentiated RSC progenitors. Also, we found COCO is required during the entire differentiation period to specify the cone fate. This suggests the cone fate is the default differentiation program of retinal progenitors, which is instructed via the absence of extrinsic cues. Together, these results provide novel insights into the mechanisms regulating RSC quiescence, proliferation and differentiation in vitro and in vivo. iii Acknowledgements I dedicate this thesis to the memory of my mom, Joan AKA Jzen, who I lost recently due to complications of ALS. I know she would have been very proud to see me complete this journey, during which she has been a limitless source of comfort and resolve. My mom radiated a profound and doting love for me and my brother that always has, and always will, suffuse my life with an unfaltering sense of gratitude. Her parting wisdom to us was to “always be true to yourself” and those were truly words she lived by. She had an unapologetically unique and indominable spirit, yet an extraordinarily gentle and kind heart. She also instilled in me an open mind, an understanding that not everything has an answer but to always keep asking questions. Thank you, mom. I will forever hold dear the love and light you brought to my life. My PhD has been as much about learning from the trial and error of experimentation and reading literature, as it has been about learning from my exceptionally inspiring and insightful colleagues, friends and mentors along the way. Foremost, I would like to thank my supervisor, Derek van der Kooy. Derek’s enthusiasm and aptitude for science has been a constant source of inspiration and motivation. His own passion and curiosity translate into his mentorship style, which encourages independent thought and exploration while also offering earnest critique and guidance. And when things have gotten tough, Derek has afforded me a tremendous amount of patience and understanding that has helped me push through. Derek has also made my time in his lab a wellspring of opportunity to develop into a well-rounded scientist through experiences outside of the lab – from enabling me to attend international conferences and engage with the global scientific community, being supportive of my pursuits as an educator when seeking TAships and guest lectures, to trusting me to represent the lab at meetings among CEOs in order to establish an academic-industry partnership. Derek, thank you for making my PhD such a rewarding experience, all about exploring open questions and open doors. I would also like to thank my advisory committee members Vince Tropepe, Rod Bremner and David Kaplan. You provided me with an extremely effective balance of scientific challenge and guidance that has always made me feel encouraged and eager to redouble my efforts toward achieving my goals. Thank you for your mentorship and support over all these years. To Matthias Steger and the Endogena crew: It has been a rare opportunity as a graduate student to participate in a biotech company as it is built from the ground up. I thoroughly enjoyed iv working with all of you, even when balancing my PhD work and our collaboration had me a little overwhelmed at times. I hope the future holds many exciting achievements for you all and great success for the company. To all the van der Kooy labbies that I have worked with day in and day out over the years, and all of my MoGen colleagues-cum-dear friends, you have been the single greatest source of moral support and encouragement (and perhaps on very rare occasions commiseration) that has kept me going. To my lab sis, Samantha Yammine, thanks for always looking out for me and making everyday lab life so much fun. We ended up pursuing so many endeavours/adventures together over the years, it really does feel like I had a sibling there supporting me along the way. To Brenda Coles, there would have been far less sanity and far more catastrophic failures if you weren’t always there to provide the guidance to keep things on track. Also, thanks for always being so enthusiastic to blast some tunes in the tissue culture room and help me complete an innumerable number of experiments. To my retinoids Saeed Khalili, Tahani Baakdhah, Justin Belair-Hickey and Brian Ballios: I have learned so much from you. You each bring your own unique approach and perspective to research that has truly expanded my… vision as a scientist. Justin, I can’t imagine more capable hands to be carrying the retinoid torch forward. Ahmed Fahmy, you’ve been a lovely labmate, a terrific travel buddy and I hear you’re pretty OK at being a father or something too. Krystal Jacques, it’s been fun collaborating on experiments, and I appreciate you for making me feel like I have at least some competence in the mentorship department. My main Moties, Geith Maal-Bared, Lyla El-Fayomi, and Reza Amirzadeh. Geith, whether in the lab, standing in front of an entire class explaining what they did wrong on their exam, or showing the world that science is a drag, you’ve truly enriched my experience these past years. Lyla, I was thoroughly impressed and enjoyed your debut novel and I look forward to reading all your future NYT bestselling Terminum series books. Hopefully we can soundboard more sci-fi story ideas in the future… but outside of the surgery room. Reza, it has been great fun diving into so many philosophical wormholes with you. Daniel Merritt, Glenn Wolfe and Isabel Mackay-Clackett: you didn’t think you’d worm your way out of this one, did you? Daniel, I don’t think there is a subject on which I wouldn’t be rapt to hear your thoughts. However, whether it is you or the whiskey talking I’m not entirely certain. Glenn, thanks for always giving your honest and insightful advice as the elder statesmen of the lab. Also, please give me your dog. Isabel, thanks for being a wonderful lab neighbour. I’ve really enjoyed all our chats, even if you probably haven’t enjoyed all my desk drum solos. I’d also like to thank all the undergrads who have enriched my time in the lab, especially Nelson v Bautista, whose thoughtfulness and work ethic made him a terrific collaborator and helped experiments run smoothly and successfully. To my extended lab fam – the former Zandstra crew – I cherish the time we’ve had together and your continuing friendships. To my dear friends, of both the Penetanguishene and post-Penetanguishene era, who I consider my chosen family: I have been ridiculously fortunate to have so many wonderful human beings in my life. You are a huge part of the ups in my life and I wouldn’t have the resolve to get through the downs without you – including the challenges this PhD has entailed. I’m fortunate there are so many of you, but unfortunately that means I cannot list you all. Please know that your friendship and support has meant the world to me. I look forward to all that the future has in store for us. On that note, a special shoutout to the Gruvi Institute: I’m excited to see where our open minds might take us. Jeff, Ryan and Kyle of Phantom Atlantic fame: these past few years have been a gift. This is not one of those endeavours that you look back on and realize how good you had it – I am continually thrilled by it and I get a sense of appreciation every single time we play music together.
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