title: Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons.
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.
authors.affiliation: 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.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zuo
authors.affiliation: State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Junzhan
authors.initials: J
authors.lastname: Jing
authors.affiliation: 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.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wang
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Xiong
authors.affiliation: 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.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Jinlin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: zhenchai@pku.edu.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chai
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Hongkui
authors.initials: H
authors.lastname: Deng
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects* / Q000235:genetics; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C568713:GSK1210151A; D006576:Heterocyclic Compounds, 4 or More Rings; D054852:Small Molecule Libraries; D014157:Transcription Factors