Rapid and efficient conversion of human fibroblasts into functional neurons by small molecules

Recent studies have demonstrated that human astrocytes and fibroblasts can be directly converted into functional neurons by small molecules. However, the reported reprogramming efficiency of human fibroblasts is extremely low, resulting in limited clinical application for the treatment of neurological disorders. Here, we report that human fibroblasts can be efficiently and directly reprogrammed into functional neuron-like cells (with a yield up to 82% TUJ1-positive neuron-like cells) by serially exposing cells to a combination of small molecules. These chemically induced neurons (iNs) displayed typical neuronal morphologies and showed neuronal transcriptional networks resembling human primary embryonic brain neurons. The iNs also exhibited mature firing patterns and formed functional synapse when cultured on mouse astrocytes. Importantly, the iNs can survive, mature and integrate into local circuits after transplantation into the postnatal mouse brains. Our study provides a rapid and efficient transgene-free approach for chemically generating neuron-like cells from human fibroblasts. Further, our approach offers strategies for disease modeling and drug discovery in central nervous system disorders.

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Yang Y, Chen R, Wu X, Zhao Y, Fan Y, Xiao Z, Han J, Sun L, Wang X, Dai J