Direct Induction of the Three Pre-implantation Blastocyst Cell Types from Fibroblasts

Cell Stem Cell. 2019 Jun 6;24(6):983-994.e7. doi: 10.1016/j.stem.2019.03.018. Epub 2019 Apr 25.


Following fertilization, totipotent cells undergo asymmetric cell divisions, resulting in three distinct cell types in the late pre-implantation blastocyst: epiblast (Epi), primitive endoderm (PrE), and trophectoderm (TE). Here, we aim to understand whether these three cell types can be induced from fibroblasts by one combination of transcription factors. By utilizing a sophisticated fluorescent knockin reporter system, we identified a combination of five transcription factors, Gata3, Eomes, Tfap2c, Myc, and Esrrb, that can reprogram fibroblasts into induced pluripotent stem cells (iPSCs), induced trophoblast stem cells (iTSCs), and induced extraembryonic endoderm stem cells (iXENs), concomitantly. In-depth transcriptomic, chromatin, and epigenetic analyses provide insights into the molecular mechanisms that underlie the reprogramming process toward the three cell types. Mechanistically, we show that the interplay between Esrrb and Eomes during the reprogramming process determines cell fate, where high levels of Esrrb induce a XEN-like state that drives pluripotency and high levels of Eomes drive trophectodermal fate.

Keywords: Eomes; Esrrb; early embryonic development; induced extraembryonic endoderm stem cells; induced pluripotent stem cells; induced trophoblast stem cells; inner cell mass; primitive endoderm; reprogramming; trophectoderm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastocyst / physiology*
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • Cellular Reprogramming
  • Embryo Implantation
  • Endoderm / physiology*
  • Fibroblasts / physiology*
  • Induced Pluripotent Stem Cells / physiology*
  • Mice
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Transcription Factors / metabolism
  • Trophoblasts / physiology*


  • EOMES protein, human
  • ESRRB protein, human
  • Receptors, Estrogen
  • T-Box Domain Proteins
  • Transcription Factors