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

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