Publication Type Academic Article
Authors Hergenreder E, Minotti A, Zorina Y, Oberst P, Zhao Z, Munguba H, Calder E, Baggiolini A, Walsh R, Liston C, Levitz J, Garippa R, Chen S, Ciceri G, Studer L
Journal Nat Biotechnol
Volume 42
Issue 10
Pagination 1515-1525
Date Published 01/02/2024
ISSN 1546-1696
Keywords Pluripotent Stem Cells, Neurons, Cell Differentiation
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.
DOI 10.1038/s41587-023-02031-z
PubMed ID 38168993
PubMed Central ID PMC11348887
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