CAREER: Directing Epithelial-Mesenchymal Tissue Self-Structuring and Remodeling With Multi-scale Mechanical Interactions and Principles of Mechanobiology

University Of Iowa, Iowa City IA

Investigators

Abstract

The goal of this NSF Faculty Early Career Development (CAREER) Program grant is to establish an integrated research and education program centered on understanding how physical forces contribute to the initial formation and later changes in epithelial-mesenchymal structures (EMS), such the bi-layered epidermal and dermal structure of skin. These structures are present in most body tissues and they are critical to tissue health. During the process of tissue formation, cell-to-cell and cell-to-extracellular matrix interactions combine to produce organized, functional tissues with EMS. Later in life, however, these tissues have limited capacity to regenerate themselves in response to injury, disease, or aging. Efforts to direct tissue self-structuring and remodeling for medical purposes are progressing, but they are still hampered by not knowing how the interactions between cells and matrix are coordinated biochemically and mechanically to produce a healthy tissue. These interactions are complex and produce behaviors that cannot be easily understood using a simple approach. This research will provide an essential computer model that can incorporate data and observations from different experiments into a unified picture so that basic principles of mechanobiology can be understood and used to help control tissue formation and remodeling. The project is expected to produce new discoveries and insights on the role of physical forces in epithelial-mesenchymal interactions in skin. The knowledge gained and tools developed may also be broadly applicable and useful to other parts of the body where EMS occur, such as blood vessels, lungs, intestines, and kidneys. Broader goals of the project include generating more public awareness, understanding, and excitement for how mathematics, engineering, and computer modeling can be used to simplify complex biological processes, particularly those that involve mechanical forces. Research findings from this project will be put into learning modules accessible for young students from K-12 in collaboration with the University of Iowa outreach programs. Research will also be put into undergraduate and graduate biomedical engineering courses, and into a publically accessible and freely downloadable multimedia iBook with live cell imaging and computer simulations. In vitro time-lapse imaging experiments on keratinocytes and fibroblasts will be used to develop and tune a multi-scale computational model for understanding and predicting how physical forces drive self-structuring and remodeling of EMS in skin. This will be accomplished by: (1) quantifying the effect of substrate stiffness, composition, & loading environment on mechanosensing and the self-assembly process of keratinocytes; (2) developing a mechanistic network-based model of mechanosensing keratinocytes that interfaces with an existent multi-scale model; (3) testing the hypothesis that mechanical crosstalk between keratinocytes and dermal fibroblasts influences self-structuring and EMS formation in an engineered skin system; and (4) extending the cell model to include 3D fibroblast-driven remodeling.