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Generation of human cerebral organoids with a structured outer subventricular zone

ABSTRACT: Outer radial glia (oRG) emerged during mammalian evolution as cortical progenitor cells that directly support the development of an enlarged outer subventricular zone (oSVZ) and, in turn, the expansion of the neocortex. The in vitro generation of oRG is essential to model and investigate the underlying mechanisms of human neocortex development and expansion. By activating the STAT3 pathway using LIF, which is not produced in guided cortical organoids, we developed a cerebral organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The structured oSVZ is composed of progenitor cells expressing specific oRG markers such as GFAP, LIFR, HOPX and closely matching human oRG in vivo. In this microenvironment, cortical neurons showed faster maturation with enhanced metabolic and functional activity. Incorporation of hPSC-derived brain vascular LIF-producing pericytes in cerebral organoids mimicked the effects of LIF treatment. These data indicate that the cellular complexity of the cortical microenvironment, including cell types of the brain vasculature, favors the appearance of oRG and provides a platform to routinely study oRG in hPSC-derived brain organoids.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224346 | GEO | 2024/04/15

REPOSITORIES: GEO

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Gene expression profile at single cell level of human cerebral cortical organoids with and without LIF treatment

Project description:Proper regulation of the proliferation and differentiation of radial glia (RG), the neural stem cells of the developing cortex, is fundamental for brain growth and organization. In humans, a specialized RG subtype, the outer radial glia (oRG), are abundant and give rise to diverse neuronal and glial progeny. However, the mechanisms regulating oRG development and differentiation are not fully understood. Here we investigated the regulation of oRG expansion and lineage potential by perturbing Leukemia Inhibitory Factor (LIF) signaling in the developing human cortex and in human pluripotent stem cell (PSC)-derived cortical organoids. LIF receptors are specifically expressed in oRG cells during neurogenesis, and, consistent with the previously described role of this cytokine as an activator of stem cell self-renewal, LIF treatment increased the number of oRG cells. Surprisingly, LIF treatment also increased the production of inhibitory interneurons (INs) in the cortex. Comparative transcriptomic analysis suggested that these INs resemble INs produced in the caudal ganglionic eminence (CGE). To test if oRG cells are the progenitors of these CGE-like INs, we isolated oRG cells from primary developing cortex and cultured them for several weeks with and without LIF treatment. We found that CGE-like INs were produced by oRG cells, and their abundance is increased by LIF treatment. Together, these observations suggest that LIF signaling regulates oRG lineage potential and capacity to generate CGE-like INs.

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