During development of the nervous system, a vast array of neurons will develop in discrete positions, acquire varied shapes, and establish connections with specific populations of target cells. Such spatial organization of neuronal cell fates and differentiation are generally accepted as being directed by soluble chemical signals, termed morphogens. However, it remains a significant question in biology about how embryonic cells transform morphogen information into spatial patterns of neuronal cell differentiation during the nervous system development. This goal of this project is to specifically address this significant knowledge gap by leveraging a stem cell-based development model that has been established in the investigator's laboratory. This synthetic human development model will be used as a controllable experimental system to determine how different morphogen signals control intracellular activities of key signaling pathways to regulate neuronal cell fates. The project, if successful, will foster significant progress in advancing fundamental understanding of the nervous system development, which is important for diagnosis, prevention and treatment of neurological disorders that are the result of impaired development and growth of the nervous system. The technologies developed under this project will be used to enhance K-12 outreach activities, with priority given to females and minority students, and educational opportunities for undergraduate and graduate students. Outreach activities planned for students in the Ann Arbor and Ypsilanti school districts include developing a summer intern program for high school students and developing educational modules for NanoCamps and TECH DAY events for K-12 students. Established University of Michigan undergraduate research programs will be leveraged to recruit undergraduate students to participate in the lab's research and a new course on "Stem Cell Bioengineering and Biotechnology" will be developed to prepare graduate students for emerging areas such as regenerative medicine and disease modeling.
It remains mysterious how embryonic cells transform dynamic changes in developmental signaling into spatial patterns of gene expression and cellular differentiation in a reliable and robust fashion. A fundamental goal of this project is thus to leverage recent progresses in human stem cell-based development models to study morphogen gradient-mediated embryonic patterning. Specifically, a synthetic microfluidic patterned human spinal cord model developed from human pluripotent stem cells will be leveraged as a maneuverable experimental platform for the proposed quantitative mechanistic investigations. Detailed mechanistic investigations will be conducted to elucidate how neuroepithelial cells in the human spinal cord model integrate the duration and level of morphogen signals to mediate distinct quantities and durations of key transcriptional effector activities. Furthermore, detailed mechanistic investigations will be conducted to understand how dynamic intracellular activities of key transcriptional effectors correlate with progressive emergence and fate specifications of neuronal subtypes in the human spinal cord model. Owing to its interdisciplinary nature, the proposed research will seamlessly integrate knowledge from distinct fields including stem cell biology, developmental biology, signal transduction, epithelial biology and microfluidics. The mechanistic investigations proposed in this research will provide new fundamental knowledge and novel discoveries of emergent self-organizing principles and pattering mechanisms that provide robustness and reliability to embryonic patterning, a long-standing question in biology,
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.