biostudies-literatureUnknown18(1)Rapino FIn the brain, the complement system plays a crucial role in the immune response and in synaptic elimination during normal development and disease. Here, we sought to identify pathways that modulate the production of complement component 4 (C4), recently associated with an increased risk of schizophrenia. To design a disease-relevant assay, we first developed a rapid and robust 3D protocol capable of producing large numbers of astrocytes from pluripotent cells. Transcriptional profiling of these astrocytes confirmed the homogeneity of this population of dorsal fetal-like astrocytes. Using a novel ELISA-based small-molecule screen, we identified epigenetic regulators, as well as inhibitors of intracellular signaling pathways, able to modulate C4 secretion from astrocytes. We then built a conStem cell reports237-253https://www.ebi.ac.uk/biostudies/studies/S-EPMC9860128biostudies-literatureSmall-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes.PMC9860128Beattie UKNorabuena ENatoli TAngelini GLimone FHazelbaker DSubramanian ABlank JThanos JMde Rivera HRubin LLTegtmeyer MMcCarroll SANarula JStevens BNehme RChen WRapino FBarrett LO'Neil ASheridan SDPerlis RHO'Connor EfalseSmall-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes.In the brain, the complement system plays a crucial role in the immune response and in synaptic elimination during normal development and disease. Here, we sought to identify pathways that modulate the production of complement component 4 (C4), recently associated with an increased risk of schizophrenia. To design a disease-relevant assay, we first developed a rapid and robust 3D protocol capable of producing large numbers of astrocytes from pluripotent cells. Transcriptional profiling of these astrocytes confirmed the homogeneity of this population of dorsal fetal-like astrocytes. Using a novel ELISA-based small-molecule screen, we identified epigenetic regulators, as well as inhibitors of intracellular signaling pathways, able to modulate C4 secretion from astrocytes. We then built a con2023-01-01T00:00:00Z2023 Jan2025-04-26T00:39:08.408Z2025-02-19T03:00:27.188ZS-EPMC98601283656368910.1016/j.stemcr.2022.11.018