Stem cell migration is a critical aspect of fracture and wound healing, and many emerging treatment systems require the migration of stem cells to or from implanted biomaterials. During migration through tissues, stem cells must crawl through an extracellular matrix with pores that are sometimes 100 to 1,000 times smaller than the cells themselves. Physiological tissues and their extracellular matrix often exhibit mechanical plasticity, undergoing irreversible deformations in response to mechanical force. In these tissues, cell generated forces can permanently -- or plastically -- expand pores in the matrix. Thus, the mechanical properties of the extracellular matrix, including how mechanically plastic or permanently deformable the matrix is, could play a critical role in regulating stem cell migration. The role of extracellular matrix plasticity in regulating stem cell migration will be investigated in this Faculty Early Career Development Program (CAREER) research project. The research will be integrated with both educational and outreach activities that involve the training of graduate students, undergraduates, and high school teachers. Research results will be incorporated into both undergraduate and graduate level courses. Teaching modules, including hands-on activities, suitable for high school classrooms and the broader public will be developed on the topics of biomaterials, stiffness, plasticity, and engineering models of living tissues. This integrated effort will broaden understanding regarding tissue mechanics and stem cell migration.
This project will investigate how tissue mechanical plasticity regulates stem cell migration. The researcher hypothesizes that cells, through the generation of forces, can plastically open up pores in the matrix to facilitate migration. Using biomaterials for 3D culture, 2D culture, and microchannel-based migration assays, this award will test this hypothesis through three research objectives. Objective 1 will examine the impact of matrix mechanical plasticity on stem cell migration in tunable 3D hydrogel matrices developed from both alginate and hyaluronic acid-collagen copolymers. Cell migration will be tracked and changes to the collagen architecture in the HA-col matrices will be quantified. Objective 2 will establish the impact of mechanical plasticity on stem cell migration on 2D surfaces and in microchannels using confocal fluorescence microscopy to assess measurements of migration as well as cellular and nuclear morphology. Objective 3 will elucidate the biophysical and molecular mechanisms that stem cells utilize to migrate through matrices with different levels of mechanical plasticity. In particular, matrix strains will be measured during migration and correlated with actin dynamics, cell morphologies and volume, and nuclear morphologies. Finally, 3D migration assays will be repeated while perturbing molecules to determine how they affect migration. These studies will reveal fundamental new insights into stem cell migration, which will advance knowledge of natural regenerative processes that can then be applied to advance regenerative medicine
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.
