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 |
| Date Published | 01/02/2024 |
| ISSN | 1546-1696 |
| 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 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 |