Organoid and Assembloid Technologies for Investigating Cellular Crosstalk in Human Brain Development and Disease

Human pluripotent stem cell-derived brain organoids produce a diversity of cell types that interact with each other in a complex 3D environment. Combining organoids resembling distinct areas into assembloids can be used to model aspects of interactions that occur between regions in the human brain. Organoids can be supplemented with non-central nervous system-derived cell types, including microglia and endothelial cells, to study the interplay of nervous system cells with immune cells and blood vessels. Patient-derived organoids can be genetically manipulated or infected with pathogens and subsequently used as tools for studying disease processes in a human context. The biology of the human brain, and in particular the dynamic interactions between the numerous cell types and regions of the central nervous system, has been difficult to study due to limited access to functional brain tissue. Technologies to derive brain organoids and assembloids from human pluripotent stem cells are increasingly utilized to model, in progressively complex preparations, the crosstalk between cell types in development and disease. Here, we review the use of these human cellular models to study cell–cell interactions among progenitors, neurons, astrocytes, oligodendrocytes, cancer cells, and non-central nervous system cell types, as well as efforts to study connectivity between brain regions following controlled assembly of organoids. Ultimately, the promise of these patient-derived preparations is to uncover previously inaccessible features of brain function that emerge from complex cell–cell interactions and to improve our mechanistic understanding of neuropsychiatric disorders. The biology of the human brain, and in particular the dynamic interactions between the numerous cell types and regions of the central nervous system, has been difficult to study due to limited access to functional brain tissue. Technologies to derive brain organoids and assembloids from human pluripotent stem cells are increasingly utilized to model, in progressively complex preparations, the crosstalk between cell types in development and disease. Here, we review the use of these human cellular models to study cell–cell interactions among progenitors, neurons, astrocytes, oligodendrocytes, cancer cells, and non-central nervous system cell types, as well as efforts to study connectivity between brain regions following controlled assembly of organoids. Ultimately, the promise of these patient-derived preparations is to uncover previously inaccessible features of brain function that emerge from complex cell–cell interactions and to improve our mechanistic understanding of neuropsychiatric disorders.