2. Academic Validation
  3. Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons

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

  • Cell Stem Cell. 2015 Aug 6;17(2):195-203. doi: 10.1016/j.stem.2015.06.003.
Xiang Li 1,  Xiaohan Zuo 2,  Junzhan Jing 3,  Yantao Ma 4,  Jiaming Wang 1,  Defang Liu 2,  Jialiang Zhu 1,  Xiaomin Du 1,  Liang Xiong 4,  Yuanyuan Du 1,  Jun Xu 1,  Xiong Xiao 2,  Jinlin Wang 2,  Zhen Chai 5,  Yang Zhao 6,  Hongkui Deng 7
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China and Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Center for Molecular and Translational Medicine, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China.
  • 2 Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
  • 3 State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
  • 4 The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China and Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Center for Molecular and Translational Medicine, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 5 State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: zhenchai@pku.edu.cn.
  • 6 The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China and Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Center for Molecular and Translational Medicine, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China. Electronic address: yangzhao@pku.edu.cn.
  • 7 The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China and Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Center for Molecular and Translational Medicine, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China. Electronic address: hongkui_deng@pku.edu.cn.
PMID: 26253201 DOI: 10.1016/j.stem.2015.06.003
Abstract

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.

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