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

TitleCombined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.
Publication TypeJournal Article
Year of Publication2024
AuthorsHergenreder E, Minotti AP, Zorina Y, Oberst P, Zhao Z, Munguba H, Calder EL, Baggiolini A, Walsh RM, Liston C, Levitz J, Garippa R, Chen S, Ciceri G, Studer L
JournalNat Biotechnol
Date Published2024 Jan 02
ISSN1546-1696
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 ╬▓-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.

DOI10.1038/s41587-023-02031-z
Alternate JournalNat Biotechnol
PubMed ID38168993
PubMed Central ID7552417
Grant ListR01AG054720 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
F31AG067709 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R01NS128087 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) /
MH116590 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) /
ALTF 311-2015 / / European Molecular Biology Organization (EMBO) /
C32559GG / / New York State Stem Cell Science (NYSTEM) /
P500PB_203107 / / Schweizerischer Nationalfonds zur F├Ârderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) /