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NEUMANN-DISSERTATION-2019.Pdf EXPLORING SINGLE CELL NEUROCHEMISTRY WITH MULTIMODAL MALDI MS BY ELIZABETH KATHLEEN NEUMANN DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2019 Urbana, Illinois Doctoral Committee: Professor Jonathan V. Sweedler, Chair Professor Martha U. Gillette Professor Mary Kraft Professor Joaquin Rodriguez-Lopez Assistant Professor Roy Dar ABSTRACT Brain function is dependent upon the active coordination of many different cell types and subtypes at cellular resolutions. While measuring neurochemistry at cellular resolutions is important for understanding emergent properties, such as cognition and memory, analyzing the chemical nature of the brain at the single cell level is primarily limited to a handful of analytical approaches which often are only capable of measuring a specific aspect of the cell. For instance, transcriptomics measures the expression level of different genes within a cell, while mass spectrometry (MS) measures gene products and metabolites themselves. Single cells are inherently sample limited, so means of extending or expanding the amount of information that can be garnered from an individual cell is important for understanding their complex neurochemistry. Here, we combine a multitude of analytical approaches with single cell matrix- assisted laser desorption/ionization (MALDI) MS to increase the amount of information we can obtain from individual mammalian brain cells. We first developed an open source software, that simplifies microscopy-guided MALDI MS measurements and subsequent correlation of data from orthogonal approaches. Using this software, we analyzed tens of thousands of rodent cerebral cells with MALDI MS and detected over five hundred distinct lipid features. Using this metabolic information, we statistically clustered the cells in 101 unique clusters, while also finding rare lipids only present in a small fraction (<1%) of cells. Further, we extended single cell MALDI MS measurements to accommodate subsequent measurements using immunocytochemistry, infrared spectroscopy, stimulated Raman scattering microscopy, single cell transcriptomics, and capillary electrophoresis, allowing us to merge the rich metabolic information detected with MS to a variety of other systems to maximize the information that can be measured from a single cell. ii ACKNOWLEDGEMENTS I would like to thank my advisor, Prof. Jonathan V. Sweedler, for the opportunity to obtain my doctorate degree within his lab and under his guidance. I appreciate his patience and support through the joys and sorrows of graduate school. I am a better person because of this experience, and I hope to use these skills and life lessons to support others and continue researching the big questions in our world. I would also like to thank the other members of my committee: Prof. Martha Gillette, Prof. Mary Kraft, Prof. Joaquin Rodriguez-Lopez, and Prof. Roy Dar, for their guidance on and enthusiasm for my dissertation work. I would also like to thank my collaborators who have made my dissertation work possible. Dr. Troy Comi initially trained me how to perform single cell MALDI MS and then became a coauthor on my manuscripts and a good friend. I greatly appreciate his endlessly patient hours coding, editing, and discussing research-related items. Joseph Ellis time and time again went with me for fish triangles, diet mountain dew, Boomerangs, and lunch. Without his company, graduate school would have been a lot duller, less enjoyable, and less successful. Marina Philip is the most supportive friend I have ever had. Thank you for always listening and never minimizing my tears and fears. I could not have made it to the end without your love and support. I will never be able to thank you enough for this. Prof. Stanislav Rubakhin was always ready to listen and provided endless advice and rodent brains. Dr. Jennifer Mitchell taught me about the neuroscience behind our work and was always willing to help whenever she could. Amelia Triplett was always happy and thankful to work on our research projects, even when I asked her to make a big table that was over a hundred pages long. I would also like to thank my other collaborators and coauthors: Prof. Bin Li, Dr. Qiyao Li, Dr. Aparna Bhaduri, Shannon Murphy, Kisurb Choe, and Sara Bell. iii I would like to thank the Women Chemists Committee, Department of Chemistry Graduate Student Advisory Committee, and First Christian Church for all the opportunities to serve my department and community. These opportunities continually reminded me of my love for science and why I wanted my doctorate degree in the first place. I especially want to thank Dr. Lloyd Munjanja for believing in and continuing the work we have started to ensure that anyone, regardless of race, gender, orientation, or background, can work towards their own doctoral degree. I would also like to thank the Women’s Resources Center, McKinley Mental Health, Courage Connection, Prof. Kate Clancy, and Prof. Steve Zimmerman for supporting me and giving me the resources and strength to continue my degree. I would also like to thank my friends and family. Your endless support and love, through illness, loss, and uncertainty, have allowed me to finish obtaining my doctoral degree and become the first doctor in my family. For that undeserved gift, I am eternally grateful. iv “Be the person you needed when you were younger.” -Ayesha Siddiqi v TABLE OF CONTENTS CHAPTER 1: INTRODUCTION AND THESIS OVERVIEW ........................................1 CHAPTER 2: EXPLORING THE FUNDAMENTAL STRICTURES OF LIFE: NON- TARGETED, CHEMICAL ANALYSIS OF SINGLE CELLS AND SUBCELLULAR STRUCTURES ..................................................................................................................12 CHAPTER 3: MICROMS: A PYTHON PLATFORM FOR IMAGE-GUIDED MASS SPECTROMETRY PROFILING ..........................................................................60 CHAPTER 4: OPTICALLY GUIDED SINGLE CELL MASS SPECTROMETRY OF RAT DRG TO PROFILE LIPIDS, PEPTIDES, AND PROTEINS ............................88 CHAPTER 5: SINGLE CELL MALDI MS SUPERVISED BY IMMUNOCYTOCHEMICAL CLASSIFICATIONS .....................................................125 CHAPTER 6: LIPID ANALYSIS OF THIRTY-THOUSAND INDIVIDUAL RODENT CELLS USING HIGH-RESOLUTION MASS SPECTROMETRY .............156 CHAPTER 7: MULTIMODAL CHEMICAL ANALYSIS OF THE BRAIN BY HIGH RESOLUTION MASS SPECTROMETRY AND INFRARED SPECTROSCOPIC IMAGING .......................................................................................222 CHAPTER 8: SINGLE CELL MALDI MASS SPECTROMETRY HYPHENATED TO STIMULATED RAMAN SCATTERING MICROSCOPY FOR ENHANCED CHEMICAL COVERAGE ..............................................................................................270 CHAPTER 9: INTERROGATION OF SPATIAL METABOLOME OF GINKGO BILOBA WITH HIGH‐RESOLUTION MATRIX‐ASSISTED LASER DESORPTION/IONIZATION AND LASER DESORPTION/IONIZATION MASS SPECTROMETRY IMAGING .......................................................................................292 vi CHAPTER 1 INTRODUCTION AND THESIS OVERVIEW 1.1 Research Summary The mammalian brain is a highly complex system composed of billions to trillions of cells actively coordinated together to create emergent functions, such as learning and memory. Many of these cells have a unique function and can generally be subdivided into categories based on morphology, function, and chemical content. Because of the inherent chemical diversity within the brain, we use single cell matrix assisted laser desorption/ionization (MALDI) mass spectrometry (MS) approaches coupled to other techniques, such as immunocytochemistry (ICC) and vibrational spectroscopy, to study the chemical components of brain cells at single cell resolution. 1.2 Single Cell Analysis Cells are the functional unit of biological systems, ranging from single cell organisms to humans, and are inherently responsible for many complex, emergent functions like learning[1] and memory[2] within the mammalian brain. Cell-to-cell diversity not only allows these emergent functions, but single cell changes can result in disease and disorders,[3] such as beta cell malfunction within type-1 and type-2 diabetes.[4] This inherent complexity in biological systems demonstrates a need to study them at single cell resolutions, and the ubiquitous presence of cells require methods capable of high-throughput and robust measurements.[3] Of particular interest is the mammalian brain, as it is one of the most complex and least understood organs, partly due to its chemical, cellular, and spatial heterogeneity.[5] New measurement approaches and instrumentation are required to understand these complex phenomena, particularly at the single cell level, where many of these complex processes begin. 1 From an analytical perspective, single cells are challenging due to their inherently low volumes, difficulty in sampling specific cells, diversity, and subsequent data analysis.[6] Several techniques have become the standard for exploring single cell heterogeneity: microscopy,[7, 8] transcriptomics,[910] vibrational spectroscopy,[11,12] electrophysiology,[13,14] capillary electrophoresis,[15,16] and MS[17-22]. Each of these techniques can measure a different aspect of the cell; for instance, transcriptomics analyzes the expression of genes by measuring the RNA compliment of a cell,[23] while microscopy images the morphology and often the localization of
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