Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration

Abstract

<p id="P1">Organoid techniques provide unique platforms to model brain development and neurological disorders. While several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains respectively. Population and single-cell RNA-seq profiling combined with bulk ATAC-seq analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live-imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids, for modeling human interneuron migration, and offers deeper insight into molecular dynamics during human brain development. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/0bcacb4e-4711-4c04-8c28-0ee75c18309d/PubMedCentral/image/nihms893346u1.jpg"/> </div> </p>