Development of a validated human iPSCs-derived microglia and brain organoid co-culture platform to investigate neuro-immune interactions

The overarching goal of this project is to develop a validated human microglia and cortical brain organoid co-culture platform to investigate neuro-immune interactions. Human brain organoids are 3D self-assembled structures of brain cells derived from human pluripotent stem cells (hPSCs) that are grown in a dish. Brain organoids mimic key aspects of human brain development, which makes them an excellent model system for studying human-specific aspects of brain development and neurological disorders. However, brain organoids innately generate only ectodermal-originated brain cells not cells from other lineages such as microglia. Microglia are resident immune cells in the brain comprising about 5-10% of total cells in the human brain and play important roles in brain development, homeostasis, and neuroinflammation during pathological conditions. Therefore, establishing a platform for hPSC-derived microglia integrated into 3D human brain organoids provides unique opportunities to study human microglia and to model brain disorders. Previous studies that have shown the feasibility of generating microglia-containing organoids failed to validate the system. In this project, we aim to optimize hPSC-derived microglia and brain organoid co-culture method by systematic comparisons of different conditions and novel approaches and validate the platform by comparing it with fresh human embryonic tissue at the cellular, transcriptomic, and functional levels. Furthermore, we will develop a pipeline for bioinformatic analyses of neuron-immune interactions from transcriptomic data.