Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State

Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)...

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Published in:	Cell stem cell Vol. 21; no. 2; p. 264
Main Authors:	Li, Xiang, Liu, Defang, Ma, Yantao, Du, Xiaomin, Jing, Junzhan, Wang, Lipeng, Xie, Bingqing, Sun, Da, Sun, Shaoqiang, Jin, Xueqin, Zhang, Xu, Zhao, Ting, Guan, Jingyang, Yi, Zexuan, Lai, Weifeng, Zheng, Ping, Huang, Zhuo, Chang, Yanzhong, Chai, Zhen, Xu, Jun, Deng, Hongkui
Format:	Journal Article
Language:	English
Published:	United States 03.08.2017
Subjects:	Aging Animals Animals, Newborn Brain - cytology Cell Differentiation Cell Lineage Cell Survival Cells, Cultured Cellular Reprogramming Endoderm - cytology Extraembryonic Membranes - cytology Female Fibroblasts - metabolism Gene Expression Profiling Genomic Instability Green Fluorescent Proteins - metabolism Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Male Mice Neurons - cytology Neurons - metabolism Neurons - transplantation Transcription, Genetic long-term expansion chemical reprogramming chemically-induced XEN-like state functional neurons direct reprogramming multifunctional XEN-like state functional hepatocyte lineage reprogramming expandable XEN-like state neural reprogramming
ISSN:	1875-9777, 1875-9777
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Abstract	Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.
AbstractList	Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state. Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.
Author	Jing, Junzhan Wang, Lipeng Zhang, Xu Sun, Shaoqiang Yi, Zexuan Chang, Yanzhong Zheng, Ping Guan, Jingyang Ma, Yantao Liu, Defang Chai, Zhen Sun, Da Xu, Jun Deng, Hongkui Lai, Weifeng Xie, Bingqing Jin, Xueqin Li, Xiang Zhao, Ting Du, Xiaomin Huang, Zhuo
Author_xml	– sequence: 1 givenname: Xiang surname: Li fullname: Li, Xiang organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China – sequence: 2 givenname: Defang surname: Liu fullname: Liu, Defang organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China – sequence: 3 givenname: Yantao surname: Ma fullname: Ma, Yantao organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China – sequence: 4 givenname: Xiaomin surname: Du fullname: Du, Xiaomin organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China; Peking University-Tsinghua University-National Institute of Biological Science Joint Graduate Program, College of Life Science, Peking University, Beijing 100871, China – sequence: 5 givenname: Junzhan surname: Jing fullname: Jing, Junzhan organization: State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China – sequence: 6 givenname: Lipeng surname: Wang fullname: Wang, Lipeng organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China – sequence: 7 givenname: Bingqing surname: Xie fullname: Xie, Bingqing organization: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China – sequence: 8 givenname: Da surname: Sun fullname: Sun, Da organization: Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China – sequence: 9 givenname: Shaoqiang surname: Sun fullname: Sun, Shaoqiang organization: State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China – sequence: 10 givenname: Xueqin surname: Jin fullname: Jin, Xueqin organization: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Health Science Center of Peking University, Beijing 100191, China – sequence: 11 givenname: Xu surname: Zhang fullname: Zhang, Xu organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China – sequence: 12 givenname: Ting surname: Zhao fullname: Zhao, Ting organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China – sequence: 13 givenname: Jingyang surname: Guan fullname: Guan, Jingyang organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China – sequence: 14 givenname: Zexuan surname: Yi fullname: Yi, Zexuan organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Peking University-Tsinghua University-National Institute of Biological Science Joint Graduate Program, College of Life Science, Peking University, Beijing 100871, China – sequence: 15 givenname: Weifeng surname: Lai fullname: Lai, Weifeng organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China – sequence: 16 givenname: Ping surname: Zheng fullname: Zheng, Ping organization: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China – sequence: 17 givenname: Zhuo surname: Huang fullname: Huang, Zhuo organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Health Science Center of Peking University, Beijing 100191, China – sequence: 18 givenname: Yanzhong surname: Chang fullname: Chang, Yanzhong organization: Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China – sequence: 19 givenname: Zhen surname: Chai fullname: Chai, Zhen email: zhenchai@pku.edu.cn organization: State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: zhenchai@pku.edu.cn – sequence: 20 givenname: Jun surname: Xu fullname: Xu, Jun organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China – sequence: 21 givenname: Hongkui surname: Deng fullname: Deng, Hongkui email: hongkui_deng@pku.edu.cn organization: Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China; MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, 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
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Keywords	long-term expansion chemical reprogramming chemically-induced XEN-like state functional neurons direct reprogramming multifunctional XEN-like state functional hepatocyte lineage reprogramming expandable XEN-like state neural reprogramming
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Snippet	Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that...
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SubjectTerms	Aging Animals Animals, Newborn Brain - cytology Cell Differentiation Cell Lineage Cell Survival Cells, Cultured Cellular Reprogramming Endoderm - cytology Extraembryonic Membranes - cytology Female Fibroblasts - metabolism Gene Expression Profiling Genomic Instability Green Fluorescent Proteins - metabolism Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Male Mice Neurons - cytology Neurons - metabolism Neurons - transplantation Transcription, Genetic
Title	Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State
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