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Mechanobiology of Brain-Derived Cells During Developmental MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES GAUTAM MAHAJAN Bachelor of Engineering in Biotechnology Engineering Panjab University May 2013 Submitted in partial fulfillment of requirements for the degree DOCTOR OF PHILOSOPHY IN APPLIED BIOMEDICAL ENGINEERING at CLEVELAND STATE UNIVERSITY December 2019 © COPYRIGHT BY GAUTAM MAHAJAN We hereby approve this dissertation for Gautam Mahajan Candidate for the Doctor of Philosophy in Applied Biomedical Engineering degree For the Department of Chemical and Biomedical Engineering and CLEVELAND STATE UNIVERSITY’s College of Graduate Studies by ________________________________________________ Chandra Kothapalli, Ph.D., Dissertation Committee Chairperson, Chemical and Biomedical Engineering, 12/9/19 ________________________________________________ Moo-Yeal Lee, Ph.D., Dissertation Committee Member, Chemical and Biomedical Engineering, 12/9/19 ________________________________________________ Nolan B. Holland, Ph.D., Dissertation Committee Member, Chemical and Biomedical Engineering, 12/9/19 ________________________________________________ Xue-Long Sun, Ph.D., Dissertation Committee Member, Chemistry, 12/9/19 ________________________________________________ Parthasarathy Srinivasan, Ph.D., Dissertation Committee Member, Mathematics, 12/9/19 This student has fulfilled all requirements for the Doctor of Philosophy degree. ________________________________________________ Chandra Kothapalli, Ph.D., Doctoral Program Director, 12/9/19 November 25, 2019 ___________________________________________ Student’s Date of Defense DEDICATION This dissertation is dedicated to my mother Poonam Mahajan, my father Inderjeet Mahajan, my brother Gaurav Mahajan, my uncle Bhushan Mahajan, my aunt Madhu Mahajan, my sister in law Rashmi Mahajan, my fiancé Akshata Datar, and my nephews Aayush & Vansh Mahajan. ACKNOWLEDGMENTS First and foremost, I thank my PhD advisor Dr. Chandra Kothapalli for providing me the opportunity to take a lead on this and numerous other projects. He has always been an incredible advisor, and without his mentoring, I could not have done what I was able to do. I would not have come this far without his constant guidance and support which helped me to develop as a researcher in the best possible way. I would also like to thank Dr. Moo- Yeal Lee, Dr. Nolan Holland, Dr. Parthasarathy Srinivasan and Dr. Xue-Long Sun, all of whom served on my committee, helped me with research questions as they came up, without which these experiments would not be possible. I would like to thank Soo-Yeon Kang for her remarkable support throughout the project. I would like to thank Dr. Tatiana Byzova from Cleveland Clinic for the opportunity to work on Kindlin mechanics project (Aim 2). Dr. Tejasvi Dudiki from Cleveland Clinic to provide cells, tissues and constant support during my PhD. I would like to acknowledge the help from Dr. Huan Liu, Dr. Jyotsna Joshi, Sean Moore, Brian Hama, Marissa Sarsfield, Akshata Datar, Jennifer Vasu, and Dr. Alex Roth. I would like to thank Dr. Pranav Joshi and Dr. Kurt Farrell for guidance and support during the initiation of this project. I would also like to thank Rebecca Laird and Darlene Montgomery and acknowledge other staff throughout the department and college who helped along the way. This work would not have been possible without the generous financial support from NIH RO1, NSF CBET, Graduate Student Research Awards (GSRA) and College of Graduate Studies. I am grateful for the depth of knowledge that I have gained and the skills that I have acquired during my time at CSU. MECHANOBIOLOGY OF BRAIN-DERIVED CELLS DURING DEVELOPMENTAL STAGES GAUTAM MAHAJAN ABSTRACT Development of nervous system has been greatly explored in the framework of genetics, biochemistry and molecular biology. With the growing evidence that mechanobiology plays a crucial role in morphogenesis, current studies are geared towards understanding the role of mechanical cues in nervous system development and progression of neurological disorders. Formation, maturation and differentiation of various development related cells are sensitive to extrinsic and intrinsic perturbations. Based on this hypothesis, the objective of this study was to investigate the effects of environmental toxicants, mutations in molecular clutch proteins, and matrix stiffness cues on the biophysical, biomechanical, and phenotypic changes in brain-derived neural progenitor cells (NPCs) and microglia. In the first aim, we established the utility of biophysical and biomechanical properties of NPCs as indicators of developmental neurotoxicity. Significant compromise (p < 0.001) in NPC mechanical properties was observed with increase in concentration (p < 0.001) and exposure duration (p < 0.001) of four distinct classes of toxic compounds. We propose the utility of mechanical characteristics as a crucial maker of developmental neurotoxicity (mechanotoxicology). In the second aim, we elucidated the critical role of molecular clutch proteins, specifically that of kindlin-3 (K3) in murine brain-derived microglia, on the cell membrane mechanics and physical characteristics. Using genetic knockouts of K3 and AFM analysis, we established the role of K3 in regulating microglia membrane mechanics. vi Mutation at the K3-β1 integrin binding site revealed that the connection serves as the major contributor of membrane to cortex attachment (MCA). Finally, in aim 3, we identified the molecular mechanisms (non-muscle myosin II) by which NPCs transduce mechanical input from external substrate into fate decisions such as differentiation and phenotype. We established cell mechanics as a label-free marker of differentiation and mechano- adaptation as possible mechanism of differentiation. Mechanical, phenotypical, and genotypical characteristics of brain-derived cells and molecular mechanisms of mechanotransduction established in this dissertation will provide important insights in various cell processes such as morphogenesis, brain plasticity, wound healing, cancer metastasis, and disease progression. vii TABLE OF CONTENTS Page ABSTRACT……….…………………………………………….…………….………….....….....vi LIST OF TABLES.……………………………………………….……….……….…………......xii LIST OF FIGURES…………………………………………….…...……………………………xiii CHAPTER I. BACKGROUND AND INTRODUCTION...………………………………..….……...…1 1.1. Role of substrate stiffness……………………...……….……………………….5 1.2. Role of integrins.….……….…………………………………..………………..5 1.3. Role of nucleus………………..……………………………………………….11 1.4. CNS and mechanobiology………….…….…………….……………………...14 1.4.1. CNS mechanical microenvironment…………………………………………..14 1.4.2. Mechanobiology of NSCs/NPCs……………………………….……………...15 1.4.3. Mechanobiology of neurons and neurogenesis………………………………..18 1.4.4. Mechanobiology of glial cells…………………………………………………20 1.4.5. CNS injury, diseases, and biomechanics………………………………………23 1.5. Approaches to study cell mechanics…………………………………………...24 1.5.1. Micropipette aspiration………………………………………………………..25 1.5.2. Optical tweezers……………………………………………………………….27 1.5.3. Magnetic twisting cytometry…………………………………………………..28 1.5.4. Microfluidics…………………………………………………………………..29 1.5.5. Atomic force microscopy……………………………………………………...31 1.6. Mechanical properties of cells…………………………………………………35 1.6.1. Cellular traction forces………….……………………………………………..35 viii 1.6.2. Cellular adhesive forces……………………………………………………….36 1.6.3. Modulus of elasticity…………………………………………………………..37 1.6.4. Tether force……………………………………………………………………38 1.6.5. Cellular deformability…………………………………………………………39 1.7. Scope of the dissertation………………………………………………………40 II. OPTIMIZATION OF AFM PROTOCOLS FOR CHARACTERIZING CELL, TISSUE AND SOFT SUBSTRATES……………………………………………..……..41 2.1. Utility of MFP-3D-Bio AFM to study mechanobiology….…...….....................41 2.2. Beading of AFM cantilever tips...…………………………....………….…….44 2.3. Spring constant calibration…...…….……………………………...……..……45 2.4. Characterization of PDMS films………………………………………………46 2.4.1. Experimental methods…………………………………………………………46 2.4.2. Results………………………………………………………………………....47 2.5. Characterization of rat-tail derived type I collagen gels.................….................48 2.5.1. Experimental methods…………………………………………………………48 2.5.2. Results…………………………………………………………………...…….49 2.6. Characterization of fixed and fresh mouse retinal tissues……………………..50 2.6.1. Methods………………………………………………………..…..………….50 2.6.2. Results………………………………………………..…………...…………...51 2.7. Characterization of fresh rat spinal cord tissues……………………………….53 2.7.1. Methods………………………………………………………..…………...…53 2.7.2. Results………………………………………………..…………...…………...55 2.8. Characterization of healthy and diseased human SMCs………………………56 2.8.1. Methods…………………………………………………………………….…56 2.8.2. Results…………………………………………………………………………57 ix 2.9. Characterization of human pediatric glioblastoma-derived cells………..……..60 2.9.1. Methods……………………………………………………………………….60 2.9.2. Results…………………………………………………………………............60 2.10. Summary…………………………………………………………………........61 III. BIOPHYSICAL AND BIOMECHANICAL PROPERTIES OF NEURAL PROGENITOR CELLS AS INDICATORS OF DEVELOPMENTAL NEUROTOXICITY……………………………………………...62 3.1. Introduction…………...……………………………..…..……………..……...62 3.2. Materials and Methods……………………….………..….…...……..…..……70 3.3. Results…………..…………………………………….……...……...………...76 3.4. Discussion.………………………………………….…….…………………...89 3.5. Conclusions…………………...…………....……..………………...……......101 IV. ROLE OF KINDLIN3 IN MEMBRANE TO CORTEX ATTACHMENT AND FORCE TRANSMISSION…………………………...……………...……....................102 4.1. Introduction……………...………………...……….……….…………..........102
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