A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids
Molly E Boutin1, Caroline E Strong2, Brittney Van Hese3
1Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA; Ecovative Design, 70 Cohoes Avenue, Green Island, NY, USA.
SLAS Discovery : Advancing Life Sciences R & D
|January 29, 2022
Summary
Three-dimensional (3D) human induced pluripotent stem cell-derived cortical spheroids offer a predictive model for neurological drug discovery. This study demonstrates their utility as a robust platform for high-throughput screening of neuroactive compounds.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Pharmacology
Background:
- Neurological disease therapeutic discovery is limited by inadequate in vitro and in vivo models.
- Traditional 2D cell cultures lack physiological relevance for neurophysiology and drug screening.
- Three-dimensional (3D) neural models from human induced pluripotent stem cells (iPSCs) show promise for studying brain development and disease.
Purpose of the Study:
- To evaluate 3D iPSC-derived cortical neural spheroids as a physiologically and pharmacologically relevant high-throughput screening (HTS) platform.
- To assess the potential of these spheroids for therapeutic development in neurological diseases.
- To demonstrate the robustness and information-rich nature of this HTS platform.
Main Methods:
- A library of 687 neuroactive compounds was screened using phenotypic assays.
- Calcium activity, measured via fluorescence, served as a functional biomarker for neural modulation.
- Pharmacological responses were analyzed using a multi-parametric approach with principal component analysis and Sammon mapping.
Main Results:
- iPSC-derived cortical spheroids exhibited spontaneous, synchronous activity, mimicking in vivo neural communication.
- The screening of 687 compounds demonstrated the platform's capacity for detecting compound responses.
- A multi-parametric analysis of calcium activity provided rich data for compound characterization.
Conclusions:
- 3D iPSC-derived cortical neural spheroids represent a robust and information-rich assay platform for high-throughput screening.
- This model system holds significant potential for advancing neurological drug discovery and therapeutic development.
- The study provides a proof-of-concept for using these spheroids in HTS paradigms.
