Upgrading the Physiological Relevance of Human Brain Organoids

The recent advent of human pluripotent stem cell (PSC)-derived 3D brain organoids has opened a window into aspects of human brain development that were not accessible before, allowing tractable monitoring and assessment of early developmental processes. However, their broad and effective use for modeling later stages of human brain development and disease is hampered by the lack of a stereotypic anatomical organization, which limits maturation processes dependent upon formation of unique cellular interactions and short- and long-range network connectivity. Emerging methods and technologies aimed at tighter regulatory control through bioengineering approaches, along with newer unbiased organoid analysis readouts, should resolve several of the current limitations. Here, we review recent advances in brain organoid generation and characterization with a focus on highlighting future directions utilizing interdisciplinary strategies that will be important for improving the physiological relevance of this model system.