학술논문
Small-molecule screen reveals pathways that regulate C4 secretion in stem cell-derived astrocytes
Document Type
article
Author
Francesca Rapino; Ted Natoli; Francesco Limone; Erin O’Connor; Jack Blank; Matthew Tegtmeyer; William Chen; Erika Norabuena; Juhi Narula; Dane Hazelbaker; Gabriella Angelini; Lindy Barrett; Alison O’Neil; Ursula K. Beattie; Jessica M. Thanos; Heather de Rivera; Steven D. Sheridan; Roy H. Perlis; Steven A. McCarroll; Beth Stevens; Aravind Subramanian; Ralda Nehme; Lee L. Rubin
Source
Stem Cell Reports, Vol 18, Iss 1, Pp 237-253 (2023)
Subject
Language
English
ISSN
2213-6711
Abstract
Summary: 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 connectivity map to predict and validate additional key regulatory pathways, including one involving c-Jun-kinase. This work provides a foundation for developing therapies for CNS diseases involving the complement cascade.