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The protracted timeline of maturation is a major bottleneck in generating adult-like neurons from human pluripotent stem cells. We identify a combination of four chemicals that promotes neuronal maturation by repressing epigenetic factors that inhibit it and stimulating activity-dependent factors that promote it.
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References
Espuny-Camacho, I. et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77, 440–456 (2013). This paper demonstrates that protracted human neuron maturation is maintained when hPSCs are transplanted into the mouse brain.
Alvarez-Dominguez, J. R. & Melton, D. A. Cell maturation: hallmarks, triggers, and manipulation. Cell 185, 235–249 (2022). A review article discussing the challenges of cell maturation across cell types.
Iwata, R. et al. Mitochondria metabolism sets the species-specific tempo of neuronal development. Science 379, eabn4705 (2023). A paper showing that mitochondrial metabolism regulates neuronal maturation.
Ciceri, G. et al. An epigenetic barrier sets the timing of human neuronal maturation. Preprint at bioRxiv https://doi.org/10.1101/2022.06.02.490114 (2022). This preprint describes detailed molecular signatures of human neuron maturation and identifies an epigenetic barrier in neural precursors that sets the pace of neuronal maturation.
Studer, L., Vera, E. & Cornacchia, D. Programming and reprogramming cellular age in the era of induced pluripotency. Cell Stem Cell 16, 591–600 (2015). A short review that lays out the broader timing challenges in human stem cell models, from fate specification to maturation and aging.
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This is a summary of: Hergenreder, E. et al. Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons. Nat. Biotechnol. https://doi.org/10.1038/s41587-023-02031-z (2024).
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Identification of a chemical cocktail that drives the maturation of human neurons.
Nat Biotechnol (2024). https://doi.org/10.1038/s41587-023-02044-8
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DOI: https://doi.org/10.1038/s41587-023-02044-8
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Margarete Fleishman