Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons Journal Article

   

Authors:	Hergenreder, E.; Minotti, A. P.; Zorina, Y.; Oberst, P.; Zhao, Z.; Munguba, H.; Calder, E. L.; Baggiolini, A.; Walsh, R. M.; Liston, C.; Levitz, J.; Garippa, R.; Chen, S.; Ciceri, G.; Studer, L.
Article Title:	Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons
Abstract:	The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription. A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-d-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages. © The Author(s) 2024. corrected publication 2024.
Keywords:	cytology; metabolism; cell differentiation; neurons; drug effect; molecular library; small molecule libraries; brain development; stem cells; pluripotent stem cell; pluripotent stem cells; amino acids; in-vitro; nerve cell; electrophysiology; pharmacology; small molecules; human brain; stem-cell; cell-based; humans; human; neurological disease; high-content; imaging assays
Journal Title:	Nature Biotechnology
Volume:	42
Issue:	10
ISSN:	1087-0156
Publisher:	Nature Publishing Group
Date Published:	2024-10-01
Start Page:	1515
End Page:	1525
Language:	English
DOI:	10.1038/s41587-023-02031-z
PUBMED:	38168993
PROVIDER:	scopus
PMCID:	PMC11348887
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85181223706&doi=10.1038%2fs41587-023-02031-z&partnerID=40&md5=3ebef74d7a5ce98a3d5d695ea057bd9b
Notes:	Article -- Erratum issued, see DOI: 10.1038/s41587-024-02233-z -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Lorenz Studer -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/220051