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Morphological Study of Cell Protrusions During Redirected Migration in Human Fibroblast Cells

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Morphological Study of Cell Protrusions During Redirected Migration in Human Fibroblast Cells MORPHOLOGICAL STUDY OF CELL PROTRUSIONS DURING REDIRECTED MIGRATION IN HUMAN FIBROBLAST CELLS Congyingzi Zhang A Thesis Submitted to the Graduate College of Bowling Green State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE August 2013 Committee: Dr. Carol Heckman, Advisor Dr. Roudabeh Jamasbi Dr. Peter Gorsevski ii ABSTRACT Carol A. Heckman, Advisor From the perspective of cell motility mechanisms, migration patterns arise from two opposing sources which can be viewed as forces. One, called intrinsic, maintains the cell persistence. The extrinsic arises from signals (repulsive or attractive) exerted by an external stimulus. The extrinsic force is stronger than the intrinsic, since it can overcome the intrinsic force and cause the cell to change direction. The current studies were designed to determine whether these forces were associated with different protrusions. I studied human fibroblast cells that collide with a haptotactic boundary between an adhesive substrate (germanium) and a non- adhesive substrate (plastic) in a chemokinesis system. The morphologies of cells migrating on the two substrates reflected the cells’ preference for the adhesive substrate. I measured the prevalence of various protrusions during the process of cells turning away from the boundary and reorienting their direction of travel. Classes that corresponded to protrusive features were identified by extracting latent factors from a number of primary, geometric variables, and included factor 4 (filopodia), factor 5 (cell mass displacement), and factor 7 (nascent neurites). The data showed that as cells moved further and further from the boundary, they had progressively lower values of factor 5. The correlation coefficient between the values is -0.4924. Factor 4 appeared to decrease near the boundary and recover as cells migrated onto the adhesive substrate. The results suggested that reorientation caused by the extrinsic force occurs by reducing filopodia and increasing cell mass displacement. It can be suggested that the simplest iii explanation for turning would be that the cell takes directional cues from the remaining filopodia and obtains redirecting force from displacements of cell mass (factor 5). iv DEDICATION To my parents, Mr. Yuwei Zhang and Mrs. Qi Zhang for their love, support, and encouragement. v ACKNOWLEDGMENTS I want to express my sincere gratitude to my advisor Dr. Carol Heckman for her continuous support of my project. She is a great advisor who always helpful and patient to me, passionate and devoted to the research, cheerful and encouraging to everyone around her. She guided me through all the stages in my research and helped me writing this report for my project. I am lucky to have her as my advisor and enjoyed all the fun from my study. I sincerely thank Dr. Roudabeh Jamasbi from the Department of Biology and Dr. Peter Gorsevski from the Department of Geology for their tremendous help in developing research methods and suggestions in writing this report. My sincere thanks to Dr. Marilyn Cayer for her help in my experiments. I also would like to thank my lab mates Dr. Mita Varghese, Dr. Surya Amarachintha, and Francis Bugyei for their cooperation in the lab. Most importantly, I want to thank my family members for their love, support, and encouragement. vi TABLE OF CONTENTS Page 1. INTRODUCTION ............................................................................................................. 1 1.1 Roles of cell migration ......................................................................................... 1 1.2 Mechanisms of cell migration and the related membrane structures ................... 2 1.3 Studies on cell redirection .................................................................................... 4 1.3.1 Haptotaxis ............................................................................................. 7 1.3.2 Chemokinesis and chemotaxis .............................................................. 9 1.3.2.1 Chemokinesis vs. Chemotaxis ............................................... 9 1.3.2.2 Studies on chemotactic attractants ......................................... 9 1.3.3 Durotaxis ............................................................................................... 11 1.4 Factors and shape analysis ................................................................................... 11 1.5 Haptotactic cell migration re-orientation model .................................................. 15 2. MATERIALS AND METHODS ....................................................................................... 17 2.1 Cells and cell culture ............................................................................................ 17 2.2 Creating the boundary between two different substrate ...................................... 18 2.3 Making cell migration tracking system ................................................................ 18 2.4 Additives to DMEM for chemokinesis ................................................................ 19 2.5 Microscopy for track and trace ............................................................................ 19 2.6 Shape analysis of track and trace ......................................................................... 20 2.7 Statistical analysis ................................................................................................ 21 3. RESULTS .......................................................................................................................... 22 3.1 Cell morphology on preferred and non-preferred substrate ................................. 22 vii 3.2 Cell migration on preferred and non-preferred substrate ..................................... 24 3.3 Cell migration redirected at haptotactic boundary ............................................... 25 3.4 Protrusions and their dependence on the distance migrated after turning ........... 29 3.5 Protrusions and their dependence on the net distance from the boundary ........... 32 4. DISCUSSION .................................................................................................................... 35 4.1 Re-orientation is characterized by cell mass displacement .................................. 35 4.2 Cell does not generate extra filopodia during re-orientation ............................... 36 4.3 Further study of filopodia sensitivity distribution from angular data .................. 38 REFERENCES ...................................................................................................................... 40 viii LIST OF FIGURES Figure Page 1 Cell migration pattern ................................................................................................ 5 2 3T3 cells crowding in the gold area of a dual substratum system ............................. 8 3 Substrate with certain elasticity mathematically modeled as a spring ....................... 13 4 Micrographs of 1000w cells with high and low factor values ................................... 15 5 Haptotactic model on a culture plate ......................................................................... 16 6 SEM micrographs of fibroblasts migrating on germanium substrate ........................ 23 7 SEM micrograph of fibroblasts on plastic substrate. ............................................... 24 8 SEM micrograph of fibroblasts growing in culture dish after 48 hours .................... 25 9 Fibroblasts from the germanium side reoriented at the haptotactic boundary ........... 27 10 Fibroblasts from the plastic side migrated across the haptotactic boundary. .......... 28 11 Schematic diagram of track length after turning and net distance from the haptotactic boundary. ....................................................... 30 12 Four factor values at cells front when the cells migrated away from the boundary 31 13 Four factor values at cells rear when the cells migrated away from the boundary .... 32 14 Four factor values at cells front with net distance between cell and the haptotactic boundary ..................................................................................... 33 15 Four factor values at cells rear with net distance between cell and the haptotactic boundary ..................................................................................... 33 Fibroblasts from the germanium side reoriented at the haptotactic boundary ........... 27 16 A model showing the most possible turning angles for a cell colliding with a haptotactic boundary ........................................................................ 37 ix 17 A fibroblast hit the haptotactic boundary with nearly 90 degree angle ..................... 38 x LIST OF TABLES Table Page 1 Definition of factors representing cell protrusions .................................................... 14 1 1. INTRODUCTION 1.1 Roles of cell migration Cell migration is an important cell behavior orchestrating various developmental, physiological, and pathological processes. For example, during gastrulation in embryogenesis, cells migrate as sheet forming new layers in embryo so as to form specialized tissue in the new sites. Additionally, neurogenesis and neuron development are closely linked with cell migration. Neuron cells have to migrate from their birth site hundreds of cell-body distances to reach the final position within the correct cortical layers which is facilitated by continual reconstruction of the cytoskeleton network [1]. Cell migration in adults is integral
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