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

• Published in: Cell stem cell 2017-08, Vol.21 (2), p.264-273.e7
• 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: Article
• Language: English
• Subjects: Aging; Animals; Animals, Newborn; Brain - cytology; Cell Differentiation; Cell Lineage; Cell Survival; Cells, Cultured; Cellular Reprogramming; chemical reprogramming; chemically-induced XEN-like state; direct reprogramming; Endoderm - cytology; expandable XEN-like state; Extraembryonic Membranes - cytology; Female; Fibroblasts - metabolism; functional hepatocyte; functional neurons; Gene Expression Profiling; Genomic Instability; Green Fluorescent Proteins - metabolism; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; lineage reprogramming; long-term expansion; Male; Mice; multifunctional XEN-like state; neural reprogramming; Neurons - cytology; Neurons - metabolism; Neurons - transplantation; Transcription, Genetic
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2017.05.019

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. [Display omitted] •Chemically induced XEN-like state is plastic to be induced into functional cell types•Functional neurons and hepatocytes are induced from the XEN-like state•XEN-like cells maintain genome stability and properties during long-term expansion In this article, Deng and colleagues show that functional neurons and hepatocytes can be induced from fibroblasts via a chemically induced and highly expandable XEN-like state, bypassing the pluripotent stage. This featured lineage reprogramming strategy would be generalized for generating other functional desirable cell types.