A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids.
Discovery of therapeutics for neurological diseases is hampered by the lack of predictive in vitro and in vivo models. Traditionally, in vitro assays rely on engineered cell lines grown two-dimensionally (2D) outside a physiological tissue context, which makes them very amenable for large scale drug...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | SLAS Discovery |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2472555222000089 |
| _version_ | 1811244518692880384 |
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| author | Molly E Boutin Caroline E Strong Brittney Van Hese Xin Hu Zina Itkin Yu-Chi Chen Andrew LaCroix Ryan Gordon Oivin Guicherit Cassiano Carromeu Srikanya Kundu Emily Lee Marc Ferrer |
| author_facet | Molly E Boutin Caroline E Strong Brittney Van Hese Xin Hu Zina Itkin Yu-Chi Chen Andrew LaCroix Ryan Gordon Oivin Guicherit Cassiano Carromeu Srikanya Kundu Emily Lee Marc Ferrer |
| author_sort | Molly E Boutin |
| collection | DOAJ |
| description | Discovery of therapeutics for neurological diseases is hampered by the lack of predictive in vitro and in vivo models. Traditionally, in vitro assays rely on engineered cell lines grown two-dimensionally (2D) outside a physiological tissue context, which makes them very amenable for large scale drug screening but reduces their relevance to in vivo neurophysiology. In recent years, three-dimensional (3D) neural cell culture models derived from human induced pluripotent stem cells (iPSCs) have been developed as an in vitro assay platform to investigate brain development, neurological diseases, and for drug screening. iPSC-derived neural spheroids or organoids can be developed to include complex neuronal and glial cell populations and display spontaneous, synchronous activity, which is a hallmark of in vivo neural communication. In this report we present a proof-of-concept study evaluating 3D iPSC-derived cortical neural spheroids as a physiologically- and pharmacologically-relevant high-throughput screening (HTS) platform and investigate their potential for use for therapeutic development. To this end, a library of 687 neuroactive compounds were tested in a phenotypic screening paradigm which measured calcium activity as a functional biomarker for neural modulation through fluctuations in calcium fluorescence. Pharmacological responses of cortical neural spheroids were analyzed using a multi-parametric approach, whereby seven peak characteristics from the calcium activity in each well were quantified and incorporated into principal component analysis and Sammon mapping to measure compound response. Here, we describe the implementation of the 687-compound library screen and data analysis demonstrating that iPSC-derived cortical spheroids are a robust and information-rich assay platform for HTS. |
| first_indexed | 2024-04-12T14:26:29Z |
| format | Article |
| id | doaj.art-8f107b8615374c78b6df830edb6875ba |
| institution | Directory Open Access Journal |
| issn | 2472-5552 |
| language | English |
| last_indexed | 2024-04-12T14:26:29Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | SLAS Discovery |
| spelling | doaj.art-8f107b8615374c78b6df830edb6875ba2022-12-22T03:29:25ZengElsevierSLAS Discovery2472-55522022-06-01274209218A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids.Molly E Boutin0Caroline E Strong1Brittney Van Hese2Xin Hu3Zina Itkin4Yu-Chi Chen5Andrew LaCroix6Ryan Gordon7Oivin Guicherit8Cassiano Carromeu9Srikanya Kundu10Emily Lee11Marc Ferrer12Division 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, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USAStemoniX, Inc, Maple Grove, Minnesota, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USAStemoniX, Inc, Maple Grove, Minnesota, USAStemoniX, Inc, Maple Grove, Minnesota, USAStemoniX, Inc, Maple Grove, Minnesota, USAStemoniX, Inc, Maple Grove, Minnesota, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USADivision of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA; Corresponding author at: National Institutes of Health, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, 9800 Medical Center Dr, Building B, Rockville, MD 20850, United States.Discovery of therapeutics for neurological diseases is hampered by the lack of predictive in vitro and in vivo models. Traditionally, in vitro assays rely on engineered cell lines grown two-dimensionally (2D) outside a physiological tissue context, which makes them very amenable for large scale drug screening but reduces their relevance to in vivo neurophysiology. In recent years, three-dimensional (3D) neural cell culture models derived from human induced pluripotent stem cells (iPSCs) have been developed as an in vitro assay platform to investigate brain development, neurological diseases, and for drug screening. iPSC-derived neural spheroids or organoids can be developed to include complex neuronal and glial cell populations and display spontaneous, synchronous activity, which is a hallmark of in vivo neural communication. In this report we present a proof-of-concept study evaluating 3D iPSC-derived cortical neural spheroids as a physiologically- and pharmacologically-relevant high-throughput screening (HTS) platform and investigate their potential for use for therapeutic development. To this end, a library of 687 neuroactive compounds were tested in a phenotypic screening paradigm which measured calcium activity as a functional biomarker for neural modulation through fluctuations in calcium fluorescence. Pharmacological responses of cortical neural spheroids were analyzed using a multi-parametric approach, whereby seven peak characteristics from the calcium activity in each well were quantified and incorporated into principal component analysis and Sammon mapping to measure compound response. Here, we describe the implementation of the 687-compound library screen and data analysis demonstrating that iPSC-derived cortical spheroids are a robust and information-rich assay platform for HTS.http://www.sciencedirect.com/science/article/pii/S2472555222000089iPSCNeural spheroidsHigh-throughput screen |
| spellingShingle | Molly E Boutin Caroline E Strong Brittney Van Hese Xin Hu Zina Itkin Yu-Chi Chen Andrew LaCroix Ryan Gordon Oivin Guicherit Cassiano Carromeu Srikanya Kundu Emily Lee Marc Ferrer A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. SLAS Discovery iPSC Neural spheroids High-throughput screen |
| title | A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. |
| title_full | A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. |
| title_fullStr | A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. |
| title_full_unstemmed | A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. |
| title_short | A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids. |
| title_sort | multiparametric calcium signal screening platform using ipsc derived cortical neural spheroids |
| topic | iPSC Neural spheroids High-throughput screen |
| url | http://www.sciencedirect.com/science/article/pii/S2472555222000089 |
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