Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons

• Published in: Cell stem cell Vol. 17; no. 2; pp. 195 - 203
• Main Authors: Li, Xiang, Zuo, Xiaohan, Jing, Junzhan, Ma, Yantao, Wang, Jiaming, Liu, Defang, Zhu, Jialiang, Du, Xiaomin, Xiong, Liang, Du, Yuanyuan, Xu, Jun, Xiao, Xiong, Wang, Jinlin, Chai, Zhen, Zhao, Yang, Deng, Hongkui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2015
• Subjects: Animals; Cell Lineage - drug effects; Cell Proliferation - drug effects; Cellular Reprogramming - drug effects; Cellular Reprogramming - genetics; Electrophysiological Phenomena - drug effects; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Profiling; Heterocyclic Compounds, 4 or More Rings - pharmacology; Mice; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Small Molecule Libraries - pharmacology; Transcription Factors - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2015.06.003

Recently, direct reprogramming between divergent lineages has been achieved by the introduction of regulatory transcription factors. This approach may provide alternative cell resources for drug discovery and regenerative medicine, but applications could be limited by the genetic manipulation involved. Here, we show that mouse fibroblasts can be directly converted into neuronal cells using only a cocktail of small molecules, with a yield of up to >90% being TUJ1-positive after 16 days of induction. After a further maturation stage, these chemically induced neurons (CiNs) possessed neuron-specific expression patterns, generated action potentials, and formed functional synapses. Mechanistically, we found that a BET family bromodomain inhibitor, I-BET151, disrupted the fibroblast-specific program, while the neurogenesis inducer ISX9 was necessary to activate neuron-specific genes. Overall, our findings provide a “proof of principle” for chemically induced direct reprogramming of somatic cell fates across germ layers without genetic manipulation, through disruption of cell-specific programs and induction of an alternative fate. [Display omitted] •Chemical screening identifies a small molecule cocktail for reprogramming•Functional mature neurons can be induced from fibroblasts with chemicals alone•BET family protein inhibition suppresses the fibroblast-specific program•The neurogenesis inducer ISX9 is required for induction of neuronal genes In this article, Deng and colleagues show that a cocktail of small molecules can drive direct lineage reprogramming of mouse fibroblasts into functional neurons, via chemical disruption of the original cell program and induction of an alternate cell fate.