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, fibroblasts, as a potentially better cell resource for transplantation, are not as easy to reprogram as astrocytes regarding their fate to neurons, and chemically induced neurons (iNs) with low efficiency from fibroblasts resulted in limited application for the treatment of neurological disorders, including depression. Here, we report that human fibroblasts can be efficiently and directly reprogrammed into glutamatergic neuron-like cells by serially exposing cells to a combination of small molecules. These iNs displayed neuronal transcriptional networks, and also exhibited mature firing patterns and formed functional synapses. Importantly, iNs could integrate into local circuits after transplantation into postnatal mouse brain. Our study provides a rapid and efficient transgene-free approach for chemically generating neuron-like cells from human fibroblasts. Furthermore, our approach offers strategies for disease modeling and drug discovery in central nervous system disorders. •Small molecules efficiently reprogram human fibroblasts into glutamatergic neurons•iNs show neuronal transcriptional networks resembling that of human primary neurons•iNs can survive, mature, and integrate into local circuits after transplantation•P7C3-A20 is the most important component of the cocktail in the reprogramming process In this article, Dai and colleagues show that human fibroblasts can be efficiently and directly reprogrammed into glutamatergic neuron-like cells by a combination of small molecules. These iNs displayed neuronal transcriptional networks, exhibited mature firing patterns and could also integrate into local circuits after transplantation. The study provides an efficient transgene-free approach for chemically generating neuron-like cells from human fibroblasts.