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Cell Stem Cell. 2019 Apr 24. pii: S1934-5909(19)30117-1. doi: 10.1016/j.stem.2019.03.018. [Epub ahead of print]

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

Author information

1
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
2
The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 9190401, Israel.
3
School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
4
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yossibug@ekmd.huji.ac.il.

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.

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

PMID:
31031139
DOI:
10.1016/j.stem.2019.03.018
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