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The Effect of Acid on the Dynamics of Intracellular Zinc and the Marker Expressions Of

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The Effect of Acid on the Dynamics of Intracellular Zinc and the Marker Expressions Of The Effect of Acid on the Dynamics of Intracellular Zinc and the Marker Expressions of Pluripotency in Somatic Cells A thesis presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Master of Science Yuli Hu April 2021 © 2021 Yuli Hu. All Rights Reserved. 2 This thesis titled The Effect of Acid on the Dynamics of Intracellular Zinc and the Marker Expressions of Pluripotency in Somatic Cells by YULI HU has been approved for the Department of Biological Sciences and the College of Arts and Sciences by Yang V. Li Professor of Biomedical Sciences Florenz Plassmann Dean, College of Arts and Sciences 3 Abstract YULI HU, M.S., April 2021, Biological Sciences The Effect of Acid on the Dynamics of Intracellular Zinc and the Marker Expressions of Pluripotency in Somatic Cells Director of Thesis: Yang V. Li Microenvironmental pH is one of the factors that affect the stability of zinc- protein binding. The tight binding between zinc and proteins is favored by the basic pH, whereas acidic pH favors a loose bound, and treatment of strong acid results in the dissociation of zinc. Physiologically, the stomach uses a very acidic pH to digest food which results in a high amount of soluble zinc in the stomach. Whether or not zinc co- present with acid and the effect of zinc on the gastric lining has rarely been discussed. In my experiments, acidic treatment induced the expression of a pluripotent marker in primary cultured gastric cells. It also stimulated the release of intracellular zinc, suggesting that acidic pH supported protein expression through dynamic zinc regulation. The overall hypothesis for my thesis is that the zinc, dissociated from acidic treatment, contributes to gene transcription or protein expression activities. This research has validated that intracellular zinc became dynamic after the acid challenge, located around the nucleus or at the endoplasmic reticulum, potentially supporting new protein machinery and production, and the intracellular dynamic zinc altered the expression profile of stem cell markers in primary cultured somatic cells. 4 Dedication I dedicate this work to my family for supporting each step I’ve taken in my career. 5 Acknowledgments Thanks to the generous fellowship support provided by the Osteopathic Heritage Foundations, Graduate Assistantship Program at Heritage College of Osteopathic Medicine (HCOM), at Ohio University. Thanks to my mentor, Dr. Yang Li, for teaching me both science and philosophy. Dr. Li has been a great support in my career development. I am very grateful for the opportunity to work with him. Thanks to Kira Slepchenko, a great friend and colleague. She taught me laboratory skills, such as Western-blot and fluorescent imaging. She is the most creative individual that I have met. Thanks to Dr. Douglas Goetz, my mentor in Biomedical Engineering, who also serves on my current thesis committee. He helped me to learn essential techniques in biology, such as ELISA, PCR, and PBMC isolation. These techniques are very helpful in the job market today. Thanks to Dr. Tomohiko Sugiyama, who serves on my thesis committee. He helps me to find out my knowledge gaps by asking me important biological questions. Thanks to Dr. Robert Colvin, who is my teacher and also serves on my thesis committee. Several years ago, Dr. Colvin left a hand-written comment on my class essay assignment saying, “Did you read all these?”. I must read cited papers carefully since then. Both Dr. Colvin and Dr. Sarah Wyatt are my favorite teachers. Dr. Wyatt teaches me to write scientifically and to think critically. She also teaches presentation skills and helps me to improve in giving talks year by year. 6 Table of Contents Page Abstract ............................................................................................................................... 3 Dedication ........................................................................................................................... 4 Acknowledgments............................................................................................................... 5 List of Tables ...................................................................................................................... 8 List of Figures ..................................................................................................................... 9 Chapter 1: Introduction ..................................................................................................... 10 1.1 Zinc Biology ......................................................................................................... 10 1.1.1 Zinc Benefits ................................................................................................ 11 1.1.2 Zinc Homeostasis ......................................................................................... 14 1.1.3 Zinc Transporters ......................................................................................... 15 1.1.4 Zinc-finger Proteins ..................................................................................... 19 1.2 Acidic Environment of Cells ................................................................................ 21 1.2.1 Homeostasis of pH in the Stomach .............................................................. 22 1.2.2 Homeostasis of pH in the Kidney ................................................................ 27 1.2.3 Homeostasis of pH in Ischemia Hypoxia..................................................... 32 1.2.4 Cellular Acidification and Intracellular Zinc ............................................... 34 1.2.5 Microenvironmental pH and Zinc-protein Binding ..................................... 35 1.3 Exploring Stem Cells ............................................................................................ 36 1.3.1 Stem Cell Division ....................................................................................... 36 1.3.2 The Induction, Identification, and Isolation of Pluripotent Stem Cells ....... 39 1.3.3 Molecular Hallmarks of Pluripotency and Their Implications .................... 43 1.3.4 Stem Cell Niches.......................................................................................... 49 1.3.5 The Doubling Time of Stem Cells ............................................................... 52 Chapter 2: Hypothesis and Specific Aims ........................................................................ 54 2.1 Hypothesis............................................................................................................. 54 2.2 Specific Aims ........................................................................................................ 54 Chapter 3: Materials and Methods .................................................................................... 55 3.1 Culture of HeLa Cells ........................................................................................... 55 3.2 Materials for the Gastric Cell Isolation and Primary Culture ............................... 55 3.3 Acidic Solution Preparation .................................................................................. 56 7 3.4 Gastric Cell Isolation and Primary Culture ........................................................... 56 3.5 Long-term Culture of the Primary Gastric Cells................................................... 57 3.6 Cell Fixation and Staining with Pluripotent Stem Cell Markers .......................... 58 3.7 Propidium Iodide (PI) Staining ............................................................................. 58 3.8 Zinc Fluorescence Staining ................................................................................... 58 3.9 Morphology Observation ...................................................................................... 59 3.10 Western Blot ....................................................................................................... 60 3.11 Wound Healing Test ........................................................................................... 60 3.12 Statistical Analysis .............................................................................................. 61 Chapter 4: Results ............................................................................................................. 62 4.1 Acid Treatments Induced the Increase of Intracellular Zinc in a pH-dependent Manner in HeLa Cells ................................................................................................. 62 4.2 The pH 3.0 Treatments Altered the Distribution of Intracellular Zinc from the Tip of HeLa Cells to the Two Sides of HeLa Cells ........................................................... 64 4.3 The Brief Acid Treatments Increased the Percentage of Spindle-shaped Cells and the Expression of Vimentin and CDK2 During the Subculture of the Acid-challenged HeLa Cells .................................................................................................................. 69 4.4 The Brief pH 3.0 Treatment Increased the Expression of SSEA-4 and Oct-4 During the Subculture ................................................................................................. 74 4.5 The Removal of Zinc by TPEN Reduced the Acid-induced Expression of SSEA-4 ..................................................................................................................................... 79 Chapter 5: Discussion ......................................................................................................
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