Summary: Researchers identified 20 drug candidates that reduce C4 immune protein secretion from astrocytes. The discovery could pave the way to treating schizophrenia and other disorders associated with C4 dysregulation in astrocytes.
Source: International Society for Stem Cell Research
Inflammation and overactivation of the immune system in the brain can cause loss of synapses and the death of neurons, leading to neurodegenerative and psychiatric diseases.
In schizophrenia, increased levels of the immune protein C4 have been measured in patients’ brains, and increasing C4 levels due to variations in copy number are associated with an increased risk for developing schizophrenia. Therapies lowering C4 levels in the brain and reducing inflammation may benefit schizophrenia patients but are currently not available.
Brain cells called astrocytes regulate the immune response and inflammatory environment in the brain by secreting immune proteins such as C4. Consequently, astrocytes are a primary target for C4-lowering therapies.
To identify effective drugs, Francesca Rapino, Lee Rubin, and colleagues from Harvard University, U.S., have developed an efficient method to make large numbers of C4-secreting human astrocytes from stem cells.
In a paper recently published in Stem Cell Reports, the researchers followed-up with a screen of 464 drugs and identified a small group of about 20 that reduced C4 secretion from astrocytes. These drugs were effective both in healthy astrocytes and in astrocytes made from schizophrenia patients’ stem cells.
This research opens up new avenues for studying inflammatory responses and their regulation in human astrocytes and serves as a platform to identify therapeutic drugs in large-scale screening approaches.
About this genetics and schizophrenia research news
Small molecule screen reveals pathways that regulate C4 secretion in stem-cell derived astrocytes
New method for 3D differentiation of astrocytes from pluripotent stem cells
Transcriptional profiling identified these cells as dorsal fetal-like astrocytes
ELISA-based small-molecule screen identified regulators of C4 secretion
Connectivity map analysis identified additional pathways that regulate C4
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.