Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output.
Stefano L Giandomenico, Susanna B Mierau, George M Gibbons, Lea M D Wenger, Laura Masullo, Timothy Sit, Magdalena Sutcliffe, Jerome Boulanger, Marco Tripodi, Emmanuel Derivery, Ole Paulsen, Andr��s Lakatos, Madeline A Lancaster
Author Information
Stefano L Giandomenico: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
Susanna B Mierau: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
George M Gibbons: John van Geest Centre for Brain Repair and Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Lea M D Wenger: John van Geest Centre for Brain Repair and Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Laura Masullo: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
Timothy Sit: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Ole Paulsen: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. ORCID
Andr��s Lakatos: John van Geest Centre for Brain Repair and Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. ORCID
Madeline A Lancaster: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK. mlancast@mrc-lmb.cam.ac.uk. ORCID
Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air-liquid interface culture to cerebral organoids, leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies, including long-range projection within and away from the organoid, growth-cone turning, and decussation. Single-cell RNA sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and subcortical projecting tracts can innervate mouse spinal cord explants and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease.
