Stem cells could help identify new drugs for schizophrenia

TECHNOLOGY

Summary: The researchers identified 20 drug candidates that reduce secretion of the immune protein C4 from astrocytes. The discovery could pave the way for the treatment of schizophrenia and other disorders associated with dysregulation of C4 in astrocytes.

Source: International Society for Stem Cell Research

Inflammation and overactivation of the immune system in the brain can cause synapse loss and neuron death, leading to neurodegenerative and psychiatric illnesses.

In schizophrenia, increased levels of the immune protein C4 have been measured in the brains of patients, and increasing levels of C4 due to copy number variations are associated with an increased risk of developing schizophrenia. Therapies that lower C4 levels in the brain and reduce inflammation may benefit patients with schizophrenia, but are not currently available.

Brain cells called astrocytes regulate the immune response and inflammatory environment in the brain by secreting immune proteins like C4. Consequently, astrocytes are a primary target for C4-lowering therapies.

To identify effective drugs, Francesca Rapino, Lee Rubin and colleagues at Harvard University, in the United States, developed an efficient method to produce a large number of C4-secreting human astrocytes from stem cells.

Human astrocytes were produced from iPSCs using 3D methods described in the article. Astrocytes were then stained with antibodies against C4 (green; the target of the work), ALDH1L1 (red; a marker for astrocytes) and DAPI (blue – which looks purple in the image – a nuclear marker). Credit: Francesca Rapino, Harvard University, USA

In an article recently published in Stem Cell Reports, researchers followed a screen of 464 drugs and identified a small group of about 20 that reduced astrocyte C4 secretion. These drugs were effective both in healthy astrocytes and in astrocytes made from stem cells from patients with schizophrenia.

This research opens 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

Author: Press office
Source: International Society for Stem Cell Research
Contact: Press Office – International Society for Stem Cell Research
Image: Image is credited to Francesca Rapino, Harvard University, USA

Original search: Free access.
“Small molecule screening reveals pathways that regulate C4 secretion in stem cell-derived astrocytes” by Lee L. Rubin et al. Stem Cell Reports


Summary

Small molecule screening reveals pathways that regulate C4 secretion in stem cell-derived astrocytes

See too

This shows a brain wiring diagram of the brain

Highlights

  • New method for 3D differentiation of astrocytes from pluripotent stem cells
  • Transcription profiling identified these cells as dorsal fetal astrocytes
  • ELISA-based small molecule screening identified regulators of C4 secretion
  • Connectivity map analysis identified additional pathways that regulate C4

Summary

In the brain, the complement system plays a crucial role in the immune response and synaptic clearance during normal development and in disease.

Here, we sought to identify pathways that modulate complement component 4 (C4) production, 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. The transcriptional profile of these astrocytes confirmed the homogeneity of this population of fetal-like dorsal astrocytes.

Using a new ELISA-based small molecule screen, we identified epigenetic regulators, as well as inhibitors of intracellular signaling pathways, capable of modulating C4 secretion from astrocytes. We then constructed a connectivity map to predict and validate additional important regulatory pathways, including one involving c-Jun kinase.

This work provides a basis for developing therapies for CNS diseases involving the complement cascade.

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