Pluripotent Stem Cell-Derived Cerebral Organoids Reveal Human Oligodendrogenesis with Dorsal and Ventral Origins

Abstract

Summary: The process of oligodendrogenesis has been relatively well delineated in the rodent brain. However, it remains unknown whether analogous developmental processes are manifested in the human brain. Here we report oligodendrogenesis in forebrain organoids, generated by using OLIG2-GFP knockin human pluripotent stem cell (hPSC) reporter lines. OLIG2/GFP exhibits distinct temporal expression patterns in ventral forebrain organoids (VFOs) versus dorsal forebrain organoids (DFOs). Interestingly, oligodendrogenesis can be induced in both VFOs and DFOs after neuronal maturation. Assembling VFOs and DFOs to generate fused forebrain organoids (FFOs) promotes oligodendroglia maturation. Furthermore, dorsally derived oligodendroglial cells outcompete ventrally derived oligodendroglia and become dominant in FFOs after long-term culture. Thus, our organoid models reveal human oligodendrogenesis with ventral and dorsal origins. These models will serve to study the phenotypic and functional differences between human ventrally and dorsally derived oligodendroglia and to reveal mechanisms of diseases associated with cortical myelin defects. : Using OLIG2-GFP knockin human pluripotent stem cell reporter lines, Jiang and colleagues demonstrate oligodendrogenesis in dorsal and ventral forebrain organoids. Furthermore, fused dorsal and ventral forebrain organoids recapitulate the developmental interactions between dorsally and ventrally derived oligodendroglia. These organoid models will serve to study heterogeneity of human oligodendroglia and to reveal mechanisms of diseases associated with cortical myelin defects. Keywords: human pluripotent stem cells, oligodendrogenesis, OLIG2, forebrain organoids, fused organoids, oligodendroglial heterogeneity