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Mechanics and Dynamics of Living Mammalian Cytoplasm JUN 2 12017 Mechanics and Dynamics of Living Mammalian Cytoplasm by Satish Kumar Gupta Bachelor of Technology in Mechanical Engineering National Institute of Technology, Durgapur, 2014 Submitted to the Department of Mechanical Engineering in partial fulfillment of the requirements for the degree of Master of Science in Mechanical Engineering at the Massachusetts Institute of Technology June 2017 2017 Massachusetts Institute of Technology. All rights reserved. Signature of Author... Signature red.acredacted Department of Mechanical Engineering May 12, 2017 Certifiedby......................... Signature redacted Ming Guo Professor of Mechanical Engineering -- A Thesis Supervisor Signature redacted A ccepted b y ................................................ --- -- -- ----- - -14 - - Rohan Abeyaratne Chairman, Department Committee on Graduate Students M S INSTITUTE OF TECHNOLOGY JUN 2 12017 LIBRARIES ARCHIVES 2 Mechanics and Dynamics of Living Mammalian Cytoplasm by Satish Kumar Gupta Submitted to the Department of Mechanical Engineering on May 1 2 th, 2017 in Partial Fulfillment of the Requirements for the Degree of Master of Science in Mechanical Engineering ABSTRACT Passive microrheology, a method of calculating the frequency dependent complex moduli of a viscoelastic material has been widely accepted for systems at thermal equilibrium. However, cytoplasm of a living cell operates far from equilibrium and thus, the applicability of passive microrheology in living cells is often questioned. Active microrheology methods have been successfully used to measure mechanics of living cells however, they involve complicated experimentation and are highly invasive as they rely on application of an external force. In the first part of this thesis, we propose a high throughput, non-invasive method of extracting the mechanics of the cytoplasm using the fluctuations of tracer particles. Using experimental and theoretical analysis, we demonstrate that the cytoplasm of a living mammalian cell behaves as an equilibrium material at short time scales. This allows us to extract high frequency mechanics of the cytoplasm using the generalized Stokes-Einstein relationship. The results obtained are in excellent agreement with our independent optical tweezer measurements in this equilibrium regime. Studies often assume cytoplasm as an isotropic material. However, under various physiological processes such as migration, blood flow on endothelial cells, it can undergo morphological changes which can induce significant redistribution of the cytoskeleton. Evidence of induced anisotropy for cells under mechanical stimuli exists however, the role of cytoskeletal restructuring on mechanical anisotropy remains unclear. Moreover, the effect of this restructuring on intracellular dynamics and forces remains elusive. In the second part of this thesis, we confine the cells in different aspect ratio and measure the mechanics of the cytoplasm using optical tweezers in both longitudinal and transverse directions to quantify the degree of mechanical anisotropy. These active microrheology measurements are later combined with independent intracellular motion measurements to calculate the intracellular force spectrum using Force Spectrum Microscopy (FSM); from which the degree of anisotropy in dynamics and forces are quantified. Thesis Supervisor: Ming Guo Title: Assistant Professor of Mechanical Engineering 3 4 Acknowledgements I owe a debt of gratitude to Ming Guo, my thesis advisor, for the encouragement and help extended by him during the entire course of the work. I found a friend, philosopher and guide in him. His scientific acumen, analytical mind and methodical supervision have enabled me to complete this work in the present shape. The Department of Mechanical engineering at MIT is an extraordinary place to study and it gives me immense pleasure to express my deep sense of appreciation and gratitude to all the members. I cannot thank Leslie and Joan enough for all the support and care they have provided me over these two years and made me feel at home. During the years I have spent here I have had numerous enlightening discussions with faculty members and peers. In particular, the deliberations with Roger Kamm, Gareth McKinley, Alan Grodzinsky have been have been irreplaceable. This dissertation is incomplete without acknowledging the valuable suggestions I received from JiLiang Hu, Yiwei Li and YuLong Han. Thank you for being excellent colleagues and friends. I would like to thank members of Weitz lab at Harvard University for all the help and suggestions they have provided me over the years. In particular, working with Jing Xia, Yinan Shen, Helen Wu has been a pleasant experience. I thank my friends, both old and new for making my life a lot of fun and inspiring me to become the best version of myself. I would also like to thank Steve Wasserman for his invaluable guidance and suggestions he has offered me through many stimulating discussions on uncountable occasions during the research. Finally, I would like to thank my family, in particular, my parents, grandparents and sisters for their unconditional love and support. 5 6 Table of Contents Title Page.................................................................................... 1 Abstract...................................................................................... 3 Acknowledgements......................................................................... 5 Table of contents............................................................................ 7 List of Figures.............................................................................. 9 Citations to Previously published work............................................... 13 Chapter 1. Introduction.................................................................. 15 1.1 Introduction and Motivation........................................................... 15 Chapter 2. Materials and Methods..................................................... 17 2.1 Cell culture, microinjection, and pharmacological Interventions................ 17 2.1.1 Cell Culture........................................................................... 17 2.1.2 Microinjection........................................................................ 17 2.1.3 Phagocytosis.......................................................................... 18 2.1.4. Pharmacological Interventions.................................................... 18 2.2. Micro-contact printing................................................................ 18 2.3. Intracellular particle tracking......................................................... 19 2.4. Active microrheology using optical tweezers...................................... 19 2.5 Immunofluorescence, microscopy and image processing......................... 20 Chapter 3. Equilibrium and non-equilibrium cell mechanics..................... 21 3.1 Introduction.............................................................................. 21 3.2 Results and Discussion................................................................ 23 3.3. Conclusion.............................................................................. 33 Chapter 4. Anisotropic Mechanics and Dynamics of Cytoplasm................ 35 4.1 Introduction.............................................................................. 35 4.2 Results.................................................................................... 37 4.2.1 Cell aspect ratio modifies cytoskeletal organization............................. 37 4.2.2. Cell aspect ratio induces anisotropy in cytoplasmic mechanics............... 40 4.2.3. Cell aspect ratio regulates cell volume and nuclear volume................... 42 4.2.4 Cell aspect ratio regulates anisotropy in intracellular motion.................. 43 4.2.5 Microtubules alignment modulates anisotropy in intracellular motion........ 45 4.2.6 Cell aspect ratio regulates anisotropy in intracellular force..................... 44 4.3 Discussion............................................................................... 49 Bibliography................................................................................ 53 7 8 List of Figures Figure 3.1. (a). Bright-field image of a living A7 cell with injected beads. (Scale bar: 10 pm.) (b). Typical trajectories of a 500 nm PEG coated particle in untreated and ATP depleted A7 cells. (Scale bar: 0.2im.) ............................................ 25 Figure 3.2. Two-dimensional MSD (Ar 2 (r)) of 500 nm tracer particles plotted against lag time on logarithmic scale in untreated A7 cells (red circle), ATP depleted A7 cells (black diamond) and noise floor (gray triangle).........................................25 Figure 3.3. (a). Schematic diagram of optical tweezers used to measure cytoplasmic moduli. (Inset): Schematic illustration of the cytoplasmic environment that the probe bead experiences. (b). Cytoplasmic moduli measured by active microrheology using optical tweezers for untreated A7 cells (red circles) and ATP Depleted A7 cells (black squares)...............................................................................27 Figure 3.4. (a) Cytoplasmic moduli measured by active microrheology using optical tweezers for different concentrations of PEG300. (b) Two-dimensional MSD (Ar2 (r)) of tracer particles plotted against lag time on logarithmic scale for different PEG concentrations. (c) The MSD data depicted in (b) is scaled with K2 for different concentrations of PEG where K.= 8.6382, 12.059 and
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