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

Hana Benchetrit, Mohammad Jaber, Valery Zayat, Shulamit Sebban, Avital Pushett, Kirill Makedonski, Zvi Zakheim, Ahmed Radwan, Noam Maoz, Rachel Lasry, Noa Renous, Michal Inbar, Oren Ram, Tommy Kaplan, Yosef Buganim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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. Benchetrit and colleagues identified a combination of factors that can produce the three in vitro equivalent cell types of the blastocyst, iPSCs, iTSCs, and iXENs, from fibroblasts. They found that Esrrb was most potent in inducing pluripotency by the activation of a XEN-like state and Eomes most potent in promoting trophectoderm fate.

Original languageAmerican English
Pages (from-to)983-994.e7
JournalCell Stem Cell
Volume24
Issue number6
DOIs
StatePublished - 6 Jun 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s)

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

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