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Comparative Biology of Aging Through the Lens of Induced Pluripotent Stem Cells

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Comparative Biology of Aging Through the Lens of Induced Pluripotent Stem Cells Skolkovo Institute of Science and Technology COMPARATIVE BIOLOGY OF AGING THROUGH THE LENS OF INDUCED PLURIPOTENT STEM CELLS Doctoral Thesis by ALEKSEI MIKHALCHENKO DOCTORAL PROGRAM IN LIFE SCIENCES Supervisors Professor Vadim Gladyshev Professor Philipp Khaitovich Moscow - 2018 © Aleksei Mikhalchenko 2018 Abstract Many of the previous attempts to uncover mechanisms of aging focused on a few traditional model organisms, such as nematodes, yeast, fruit flies, and mice. However, considering the incredible diversity of lifespan across phylogeny, all these species are short-lived and therefore, by their nature, are less effective in resisting deleterious changes during aging. An alternative approach is to employ comparative biology of aging, taking advantage of exceptionally long-lived species and uncovering relevant molecular mechanisms underlying their longevity. In this work, we initially focused on induced pluripotent stem cells (iPSCs) as a new tool for comparative aging studies. The use of iPSCs may address challenges associated with limited availability of biological samples from non-traditional species. We first used mouse and rat species to master our iPSC skills. We then developed a robust protocol for efficient generation of iPSCs from the longest-lived rodent, the naked mole rat (NMR). We generated and characterized these cells and performed comparative gene expression analyses involving mouse, human and NMR iPSCs. We also characterized the generated rat and NMR iPSCs for naïve pluripotency by examining their ability to contribute to embryonic interspecific chimeras via the injection of iPSCs to mouse blastocysts. To comparatively analyze interspecific chimeras involving long- and short-lived species, we developed full-term chimeras between rat and mouse. We further examined aging-related features using this rat-mouse model. Finally, as low body temperature is known to benefit lifespan, we examined the link between thermoregulation and aging by performing comparative studies on thermogenesis between homeothermic mouse and poikilothermic NMR. We confirmed pluripotency of established mouse, rat, and NMR iPSCs and uncovered unique features of NMR iPSCs such as a propensity for a tetraploid karyotype and resistance to forming teratomas. Comparative gene expression analyses of NMR 2 iPSCs placed them close to human than mouse iPSCs. Remarkably, not only the rat, but also NMR iPSCs successfully contributed to embryonic interspecific chimeras indicating the potential to create paradigm-shifting chimeric models between long- and short-lived species. Analysis of age-associated changes in rat-mouse chimeras revealed a decrease of chimerism over the lifetime. We also uncovered active thermogenesis in the NMR, although heat loss appears to preclude homeothermy in these animals. The establishment of iPSCs from extremely long-lived animals, the development of relevant interspecific chimeric models, and advances in comparative analyses of thermogenesis open new opportunities for understanding the exceptional traits of longevity outliers. 3 Publications 1. Sang-Goo Lee#, Aleksei Mikhalchenko#, Sun Hee Yim, Alexei V. Lobanov, Jin-Kyu Park, Kwang-Hwan Choi, Roderick T. Bronson, Chang-Kyu Lee, Thomas J. Park, Vadim N. Gladyshev (2017) Naked mole rat induced pluripotent stem cells and their contribution to interspecific chimera. Stem Cell Reports 9, 1706-1720, # Authors contributed equally to this work 2. Sang-Goo Lee#, Aleksei Mikhalchenko#, Sun Hee Yim, Vadim N. Gladyshev (2018) A naked mole rat iPSC line expressing drug-inducible mouse pluripotency factors developed from embryonic fibroblasts. Stem Cell Research 31, 197-200. # Authors contributed equally to this work 4 Acknowledgements This work was performed in 2015-2018 in the laboratory of Professor Vadim Gladyshev in the Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School. I want to express my deepest gratitude to Professor Vadim Gladyshev for providing the opportunity to work in his lab and for his continuous support and guidance towards my PhD. I am forever grateful. I also thank my Skoltech advisor, Professor Philipp Khaitovich, as well as the Skoltech Center of Life Sciences and the Department of Education for their financial support and the opportunity to carry out my research in the lab of Professor Gladyshev. There is no better place in Russia for innovative graduate research. I would further like to express my very special thanks to Dr. Sang-Goo Lee for being my mentor and sharing his broad experience in the stem cell field, as well as for the numerous exciting discussions. It was a great pleasure working with and learn from him. Next, I would like to thank Dr. Sun Hee Yim and Dr. Zalán Péterfi for their professional help and assistance with the experiments. Without their contribution, this dissertation would not be possible. I am also grateful to all current and former members of the Gladyshev lab for their helpful comments and stimulating discussions during lab meetings. I would also like to thank all the colleagues and collaborators at Brigham and Women’s Hospital, Harvard, the Broad Institute of MIT and Harvard, University of 5 Rochester, Whitehead Institute for Biomedical Research, and University of Illinois at Chicago, with whom I had a pleasure to meet and collaborate. I also want to express my gratitude to Prof. Alexander Banks (Brigham and Women’s Hospital, Harvard Medical School) for his help with and contribution to thermogenesis studies. Finally, I am incredibly thankful to my family and friends, who have been supporting me all these years. 6 Table of Contents ABSTRACT ............................................................................................................................... 2 PUBLICATIONS ......................................................................................................................... 4 ACKNOWLEDGEMENTS ............................................................................................................ 5 TABLE OF CONTENTS ............................................................................................................... 7 LIST OF SYMBOLS, ABBREVIATIONS ......................................................................................... 9 LIST OF FIGURES ..................................................................................................................... 11 LIST OF TABLES ....................................................................................................................... 14 CHAPTER 1 REVIEW OF THE LITERATURE ................................................................................ 15 THE NAKED MOLE RAT AS A MODEL ORGANISM FOR COMPARATIVE STUDIES ON AGING AND LONGEVITY .... 16 Naked mole rat habitat and eusociality ................................................................................ 17 Unique traits of naked mole rats .......................................................................................... 19 Naked mole rat thermoregulation ........................................................................................ 22 Induced pluripotent stem cells as a source for comparative aging studies .......................... 26 PLURIPOTENCY, PLURIPOTENT STEM CELLS, AND INTERSPESIFIC CHIMERAS ............................................. 28 Embryonic origin of pluripotency .......................................................................................... 28 Captured or induced pluripotency in vitro ............................................................................ 29 Characteristics of PSCs from different species ...................................................................... 31 Reprogramming to iPSCs ...................................................................................................... 36 Interspecific mammalian chimeras ....................................................................................... 41 CHAPTER 2 NAKED MOLE RAT INDUCED PLURIPOTENT STEM CELLS AND THEIR CONTRIBUTION TO INTERSPECIFIC CHIMERA ................................................................................................... 44 ABSTRACT .................................................................................................................................... 45 INTRODUCTION ............................................................................................................................. 46 7 RESULTS ...................................................................................................................................... 49 DISCUSSION .................................................................................................................................. 77 MATERIALS AND METHODS ............................................................................................................. 82 CHAPTER 3 AGE-RELATED CHANGES IN A RAT-MOUSE CHIMERIC MODEL .............................. 93 ABSTRACT .................................................................................................................................... 94 INTRODUCTION ............................................................................................................................. 95 RESULTS ...................................................................................................................................... 97 MATERIALS AND METHODS ..........................................................................................................
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