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

Nat Biotechnol. 2024 Oct;42(10):1515-1525. doi: 10.1038/s41587-023-02031-z. Epub 2024 Jan 2.

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.

MeSH terms

  • Cell Differentiation* / drug effects
  • Humans
  • Neurons* / cytology
  • Neurons* / drug effects
  • Neurons* / metabolism
  • Pluripotent Stem Cells* / cytology
  • Pluripotent Stem Cells* / drug effects
  • Small Molecule Libraries / pharmacology

Substances

  • Small Molecule Libraries