RECODE: New technologies to illuminate and harness cadherins for the reproducible production of cortical tissue in human cerebral organoids

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Brain organoids are clusters of cells that mimic many features of the human brain. As human stem cells differentiate into brain cells, these clusters form. Experimenting on human brains poses many challenges. As a result, brain organoids are used in place of the brain in many studies of early brain development, neurological disorders, and drug discovery research. High variability in the production of brain organoids limits the usefulness in these studies. The goal of this project is to reduce variability through control of cell-cell adhesion during organoid development. The expected outcome will be a collection of cell-cell adhesion interventions that broadly improve the reproducibility of brain organoids production so they can be used as reliable models for human neural development and disease. As part of the project, graduate and undergraduate students will be mentored in team leadership across diverse fields of stem cell biology and engineering.Cell-cell adhesion dynamically remodels the brain during development. Our central hypothesis is that modulation of cell-cell adhesion can manufacture reproducible cerebral organoids from any human stem cell line. New tools to systematically interrogate and modulate cell-cell adhesion at different stages of cerebral organoid differentiation will be developed and implemented. This will be achieved with three specific aims: (1) Develop a suite of technologies to control cell-cell adhesion in human pluripotent stem cells; (2) Identify mechanisms by which cell-cell adhesion regulates neuronal differentiation; and (3) Measure changes in reproducibility upon differentiation with new cell-cell adhesion modulation protocols. The expected outcomes of this project include fundamental knowledge of the role of cell-cell adhesion at early stages of human neuronal differentiation; new technologies to modulate cell-cell adhesion; new technologies to culture and monitor organoids; and a workable differentiation strategy for cerebral organoid development across human pluripotent stem cell lines. These new tools and insights can likely be translated to understand adhesion-based morphogenesis in the differentiation of many cell types beyond cerebral organoids.This project is being jointly supported by the Engineering Biology and Health Cluster in ENG/CBET and the Biomechanics and Mechanobiology Program in ENG/CMMI.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.