Volume 27, No 3, Mar 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 3, March 2017: 386-401

ORIGINAL ARTICLES

A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations

Xiaoping Han^1,2,10,11, Hao Yu³, Daosheng Huang^1,11, Yang Xu^1,11, Assieh Saadatpour⁴, Xia Li^1,11, Lengmei Wang⁶, Jie Yu⁵, Luca Pinello⁴, Shujing Lai^1,11, Mengmeng Jiang^1,11, Xueying Tian⁷, Fen Zhang¹, Yanhong Cen¹, Yuko Fujiwara², Wei Zhu⁶, Bin Zhou⁸, Tianhua Zhou⁹, Hongwei Ouyang^1,10, Jianan Wang^6,11, Guo-Cheng Yuan⁴, Shumin Duan³, Stuart H Orkin^2,6 and Guoji Guo^1,2,10,11

¹Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
²Division of Pediatric Hematology/Oncology, Dana Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
³Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
⁴Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA
⁵Department of Pathology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
⁶The 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
⁷The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Shanghai 200031, China
⁸Howard Hughes Medical Institute, Boston, MA 02115, USA
⁹Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
¹⁰Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
¹¹Stem Cell Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China Correspondence: Guoji Guo, E-mail: ggj@zju.edu.cn; Stuart H Orkin, E-mail: stuart_orkin@dfci.harvard.edu; Xiaoping Han,(xhan@zju.edu.cn)

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.

10.1038/cr.2017.17

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