Biomechanical Regulation in Human Neural Induction

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Neural tube defects are among the most common birth defects and affect more than 500,000 infants worldwide each year. Neural tube defects can result in severe health problems, including paralysis of legs, brain damage, and even death. To develop novel approaches for the prevention and diagnosis of neural tube defects, a fundamental understanding of the development of the central nervous system is required. Using animal models, genetic and biochemical factors that regulate neural induction, the first stage of the central nervous system development, have been partially unraveled. Recent studies suggest that the cell fate decision in the neural induction is regulated by biomechanical cues. This mechanical mechanism is poorly understood and very difficult to study using animal models. This research will build a series of novel cell culture tools to investigate the genetic, biochemical and biomechanical interactions during neural induction. These new tools will provide the ability to perform experiments with lower costs and not using animal subjects to determine the mechanical effects on neural tube formation. Fundamental data on how the mechanical environment of the cells changes their behavior during neural tube development will be collected. The principal investigator will engage K-12, undergraduate and graduate students with diverse ethnic backgrounds and genders with this interdisciplinary bioengineering research, and encourage them to pursue science and engineering careers.This project will test the hypothesis that mechanical interactions dictate morphogenic events in neural development. Micropatterned cell culture environments are known to cause human cells to mimic the spatial patterning of neuroepithelial cells and neural plate border cells of the neural plate, and thus will be used to model neural induction. Drug treatment and a novel device which locally expands the cells located in the designated regions of micropatterns to dynamically regulate cell shape and force will be used to investigate how cell spatial patterning in the in vitro neural induction model regulates cell shape and force. The mechanotransduction pathways in neural induction will be investigated, focusing on the functional involvement of YAP, BMP and Wnt signals. Lastly, a radial chemical gradient generation device integrated with the micropatterning platform will be developed to interrogate whether biochemical gradient can also induce cell spatial patterning during neural induction, and whether cell shape and force act downstream of biochemical gradient or work independently to determine lineage specification. Using integrative microsystems with the capability to fine-tune chemical and mechanical environment, this research provides for the first time a quantitative analysis of the interactions between biochemical and biomechanical cues in neural development.