The Role of Cellular Mechanical Oscillations in Triggering Cell Migration

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This award will study cellular mechanical oscillations, which exist broadly in many cell types. In migrating cells (cells that are able to move from one location of the body to another), mechanical oscillations of cells are thought to contribute to disease development, such as cardiovascular disease and cancer by triggering cell migration. However, a critical gap exists in understanding how these cellular mechanical oscillations are regulated, and thus trigger cell migration. Continued existence of this knowledge gap hinders the development of therapies to prevent and treat human disease. This study seeks to elucidate the molecular mechanism of cellular mechanical oscillations and their functions in cell migration. Scientific outcomes of this work are expected to advance efforts to treat and prevent cell migration-relevant diseases. This work also advances undergraduate and graduate education and training in bioengineering in South Dakota. Mentoring and authentic research experiences will be provided to undergraduate students from groups historically underrepresented in STEM. In particular, in collaboration with a local tribal college and a primarily undergraduate institution, a discovery-based program will be advanced to attract Native American, female, and first-generation students to pursue careers in biomedical engineering. This work answers a central question: What is the underlying mechanism and function of cellular mechanical oscillations, and how do physicochemical stimuli regulate them? The hypothesis is cellular mechanical oscillations are driven by cytoskeletal remodeling and oscillation in cell adhesion force, which, in turn, synergistically regulates cell polarization and migration. This hypothesis will be addressed by three research objectives. First, the work will decipher the underlying mechanism by which cytoskeletal remodeling and vinculin vibration drive periodic oscillations in cell mechanics. Second, the work will elucidate the relationship between oscillations in cell mechanics, polarization, and migration. Third, the work will discover how physicochemical signals regulate cellular mechanical oscillations and cell migration. An innovative approach is employed that integrates: (a) real-time fluorescence-lifetime imaging microscopy to monitor cytoskeleton dynamics; (b) real-time cellular E-modulus-mapping and height-mapping using atomic force microscopy to monitor cellular mechanical oscillations and cell membrane undulation; and (c) data-driven mathematical models for signal and image processing. For the first time, this study will link cellular mechanical oscillations to cell membrane undulation, cell polarization, and then to cell migration. Findings are expected to provide fundamental new understanding of cellular mechanical oscillations and inform development of new strategies to treat human disease, such as cardiovascular disease and cancer metastasis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.