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The Role of Cell-Substrate Interactions in ECM Remodeling, Migration, and the Formation of Multicellular Structures

Reinhardt, James W
http://rave.ohiolink.edu/etdc/view?acc_num=osu1417701676

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Active, mechanical interactions between cells and their extracellular matrix (ECM) are essential for ECM remodeling and cell migration, two behaviors that support diverse biological processes including embryonic development, wound healing, fibrosis, and cancer progression. Cell-populated reconstituted type I collagen hydrogels are often used as a model system in which to study ECM remodeling and cell migration in vitro. Unfortunately, this system has limitations since it is not possible to independently control individual microstructural properties. This limitation has inspired theoretical models as an alternative way to study ECM remodeling and migration. However, so far no single approach has been able to capture both fibril-level detail and dynamic cell traction force. With the goal of creating a model that can capture both fibril-level detail and dynamic cell traction force, we developed an agent-based model of cell-mediated collagen compaction and migration. With this model we observed behaviors that were not programmed, but emerged from simple rules for cell-fibril interactions. Among these, our model qualitatively reproduced remodeling commonly seen in cell-populated collagen gels: macroscopic, pericellular, and intercellular compaction. Similar to experimental observations, matrical tracks formed between pairs of cells before directional migration of nearby cells toward on another. Cells also exhibited durotaxis in the absence of force-strengthening of cell-matrix bonds. This suggests that durotaxis may not involve a complicated mechanism, but may simply be an emergent behavior, the cumulative result of analogous, simple, cell-matrix interactions. We then further developed this model to make collagen fibrils more physically-realistic by modeling them as elastic rods and using parameter values obtained from the experimental literature. Subjecting our fibrils to loading conditions that created tension and bending demonstrated that our simulated fibrils approximated their analytically-predicted deformations and shapes. Modeling of cross-links was also improved to more closely approximate their expected behavior. Together, these changes resulted in a more intentionally constructed network that was stress-free in the absence of external perturbation. Model development culminated in model validation against two sets of data from the experimental literature. Similar to experimental data our computational model showed that collagen displacement decreased linearly with increasing distance from a single cell and that the compaction of collagen between pairs of cells was inversely related to cell-cell distance. In other work we used in vitro experiments to show that PANC-1 cells did not exhibit directed migration toward a central cluster. Using agent-based modeling, we then were able to show that clustering may occur simply due to random migration, relatively high cell-cell adhesion, and low cell-matrix adhesion. Separately, I have contributed to the refinement of an experimental system used to study cell-matrix interactions that provides an alternative to reconstituted type I collagen.
Keith Gooch (Advisor)
Samir Ghadiali (Committee Member)
Richard Hart (Committee Member)
Peter Anderson (Committee Member)
189 p.
Biomedical Engineering
agent-based modeling; collagen; remodeling; migration; PANC-1; cell tracking; differential adhesion; directed migration; long-range signaling

Recommended Citations

Citations

  • Reinhardt, J. W. (2014). The Role of Cell-Substrate Interactions in ECM Remodeling, Migration, and the Formation of Multicellular Structures [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417701676

    APA Style (7th edition)

  • Reinhardt, James. The Role of Cell-Substrate Interactions in ECM Remodeling, Migration, and the Formation of Multicellular Structures. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1417701676.

    MLA Style (8th edition)

  • Reinhardt, James. "The Role of Cell-Substrate Interactions in ECM Remodeling, Migration, and the Formation of Multicellular Structures." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417701676

    Chicago Manual of Style (17th edition)

osu1417701676
665
© 2014, some rights reserved.Creative Commons License The Role of Cell-Substrate Interactions in ECM Remodeling, Migration, and the Formation of Multicellular Structures by James W Reinhardt is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.