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

          The Paper of the Day article describes a high-content screening approach to identify small molecules that can promote the maturation of human pluripotent stem cell-derived cortical neurons. The researchers developed a multi-parameter imaging assay to quantify various aspects of neuronal maturation, including neurite growth, nuclear morphology, and induction of immediate early genes. Screening a library of 2,688 bioactive compounds, they identified several hits that enhanced neuronal maturation, including inhibitors of the chromatin modifiers LSD1 and DOT1L, as well as an L-type calcium channel agonist. Combining these three compounds into a "GENtoniK" cocktail further improved multiple maturation readouts. The GENtoniK cocktail also enhanced synaptic marker expression, electrophysiological properties, and spontaneous network activity in the stem cell-derived neurons. Additionally, the GENtoniK treatment improved the maturation of stem cell-derived pancreatic beta cells and melanocytes, suggesting a broader applicability of this chemical strategy.