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

被引:40
作者
Benchetrit, Hana [1 ]
Jaber, Mohammad [1 ]
Zayat, Valery [1 ]
Sebban, Shulamit [1 ]
Pushett, Avital [1 ]
Makedonski, Kirill [1 ]
Zakheim, Zvi [1 ]
Radwan, Ahmed [1 ]
Maoz, Noam [1 ]
Lasry, Rachel [1 ]
Renous, Noa [1 ]
Inbar, Michal [1 ]
Ram, Oren [2 ,3 ]
Kaplan, Tommy [4 ]
Buganim, Yosef [1 ]
机构
[1] Hebrew Univ Jerusalem, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, Hadassah Med Sch, IL-91120 Jerusalem, Israel
[2] Hebrew Univ Jerusalem, Silberman Inst Life Sci, Edmond J Safra Campus, Edmond, OK USA
[3] Hebrew Univ Jerusalem, Edmond & Lily Safra Ctr Brain Sci, Edmond J Safra Campus, Edmond, OK USA
[4] Hebrew Univ Jerusalem, Sch Comp Sci & Engn, IL-9190401 Jerusalem, Israel
基金
以色列科学基金会; 欧洲研究理事会;
关键词
TROPHOBLAST STEM-CELLS; TRANSCRIPTION FACTORS; EXPRESSION; PLURIPOTENT; REVEALS; CONVERSION; FATE; GENE; DIFFERENTIATION; MECHANISMS;
D O I
10.1016/j.stem.2019.03.018
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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.
引用
收藏
页码:983 / +
页数:19
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