title: A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations.
abstract: Recent advances have demonstrated the power of small molecules in promoting cellular reprogramming. Yet, the full potential of such chemicals in cell fate manipulation and the underlying mechanisms require further characterization. Through functional screening assays, we find that mouse embryonic fibroblast cells can be induced to trans-differentiate into a wide range of somatic lineages simultaneously by treatment with a combination of four chemicals. Genomic analysis of the process indicates activation of multi-lineage modules and relaxation of epigenetic silencing programs. In addition, we identify Sox2 as an important regulator within the induced network. Single cell analysis uncovers a novel priming state that enables transition from fibroblast cells to diverse somatic lineages. Finally, we demonstrate that modification of the culture system enables directional trans-differentiation towards myocytic, glial or adipocytic lineages. Our study describes a cell fate control system that may be harnessed for regenerative medicine.
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Han
authors.affiliation: Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Daosheng
authors.initials: D
authors.lastname: Huang
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Assieh
authors.initials: A
authors.lastname: Saadatpour
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: The 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Lengmei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Shujing
authors.initials: S
authors.lastname: Lai
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Shanghai 200031, China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Tian
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Cen
authors.affiliation: Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: The 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: The 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Jianan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
authors.affiliation: Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|The 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.|Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.|Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Guoji
authors.initials: G
authors.lastname: Guo
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000166:cytology; D009457:Neuroglia / Q000166:cytology; D010641:Phenotype; D059010:Single-Cell Analysis; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D054852:Small Molecule Libraries