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

Cell Stem Cell. 2017 Aug 3;21(2):264-273.e7. doi: 10.1016/j.stem.2017.05.019. Epub 2017 Jun 22.


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.

Keywords: chemical reprogramming; chemically-induced XEN-like state; direct reprogramming; expandable XEN-like state; functional hepatocyte; functional neurons; lineage reprogramming; long-term expansion; multifunctional XEN-like state; neural reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Green Fluorescent Proteins