Cell-cell adhesion is a fundamental feature of multi-cellular systems. The goal of this proposal is to analyze how individual epithelial cells recognize neighboring cells to form mutual cell-cell adhesion while rejecting self-contact. Homophilic adhesive receptors on two opposing cells rapidly bind to form a cell-cell adhesion, yet the same receptors on two thin protrusions originating from the same cell surface do not. This self-awareness of individual cells suggests that cells can distinguish the chemically identical surface of neighboring cells from their own. We hypothesize that the self-recognition mechanism is mechanically regulated, and that the cadherin complex is a mechano-sensing complex that detects external forces, thereby providing a signaling cue for mutual cell adhesion. In the absence of external forces, the mechano-signal is off, and leads to the elimination of self-contacts. Using innovative micro-fabricated substrates to control self-contacting events, we will analyze the formation of self-contacts and the subsequent elimination of self-contacting sites. Furthermore, we have developed miniature force sensors to detect forces at the adhesive contacts and directly test our hypothesis. Our findings will also highlight how mutual cell-cell adhesion forms between neighboring cells. Once we understand the fundamental processes of self and other recognition by cells, our goal is to develop therapeutic agents that alter cell- cell adhesion and can be used to prevent cancer cell invasion or pathogen infection.

Public Health Relevance

Regulation of cell-cell adhesion plays critical roles in development and homeostasis of multi-cellular organisms. The goal of this proposal is to analyze how individual epithelial cells recognize neighboring cells to form mutual cell-cell adhesions while rejecting self-contact. One potential outcome of the proposed research will be the development of advanced therapeutic agents that prevent cancer cell invasion or pathogen infection.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZGM1-GDB-7 (EU))
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Nie, Zhongzhen
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University of California Davis
Biomedical Engineering
Schools of Engineering
United States
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