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hiPS Cell-Derived Neurons for High-Throughput Screening.
Stefanie Traub1, Ralf Heilker2
1Trenzyme GmbH, Konstanz, Germany.
Methods in Molecular Biology (Clifton, N.J.)
|May 25, 2019
Summary
Scalable production of human induced pluripotent stem (hiPS) cell-derived neurons using the GRINCH method enables high-throughput screening for neurodegenerative diseases. These neurons are suitable for drug discovery targeting pathways like tropomyosin receptor kinase B (TrkB).
Area of Science:
- Neuroscience
- Stem Cell Biology
- Drug Discovery
Background:
- Human induced pluripotent stem (hiPS) cells offer a promising model for studying neurodegenerative and neuropsychiatric diseases.
- Current drug discovery efforts require large quantities of reliable neuronal models.
Purpose of the Study:
- To develop a scalable protocol for generating human induced pluripotent stem (hiPS) cell-derived neurons for high-throughput screening (HTS).
- To validate the utility of these neurons in drug discovery campaigns, specifically for modulators of tropomyosin receptor kinase B (TrkB).
Main Methods:
- A neuronal differentiation protocol incorporating a cellular amplification phase for hiPS-derived neural progenitor (NP) cells, termed GRINCH (growth factor-driven expansion and inhibition of notch).
- Maturation of GRINCH cells in 384-well microplates and assessment of neuronal markers and electrophysiological activity.
- Application of amplified luminescent proximity homogeneous assay (Alpha) and high-throughput reverse transcription polymerase chain reaction (RT-PCR) for drug target profiling.
Main Results:
- The GRINCH protocol enabled scalable production of neurons suitable for HTS.
- GRINCH neurons expressed neuronal markers and exhibited electrophysiological activity.
- The protocol was effective across various hiPS cell clones and demonstrated suitability for measuring TrkB signaling.
Conclusions:
- The GRINCH method provides a scalable route to generate functional neurons from hiPS cells for drug discovery.
- This approach, combined with advanced detection technologies, offers significant potential for early-stage pharmaceutical research and development.
- The developed platform is adaptable for screening modulators of various pharmaceutical targets.
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