以色列希伯来大学哈达萨医学院的Yosef Buganim研究组取得一项新进展，他们直接将成纤维细胞诱导了三种着床前的囊胚细胞类型。这一成果于2019年6月发表在国际知名学术期刊《Cell Stem Cell》上。

受精之后，全能干细胞经历不对称细胞分裂在后期着床前囊胚中产生三种不同的细胞类型：上胚层（Epi）、原始内胚层（PrE）和滋养外胚层（TE）。

研究人员希望了解是否这三种细胞类型都能够用转录因子的组合将成纤维细胞直接诱导形成。借助于一套成熟的荧光敲入报告基因系统，研究人员鉴定到5个转录因子的组合：Gata3、Eomes、Tfap2c、Myc和Esrrb，能够将成纤维细胞同时重编程为诱导型多功能干细胞（iPSCs）、诱导型滋养层干细胞（iTSCs）以及诱导型胚外内胚层干细胞（iXENs）。进一步地转录组、染色质以及表观分析揭示了这三类细胞的重编程过程背后的分子机制。研究人员发现，Esrrb和Eomes的相互影响决定着重编程过程中的细胞命运，即Esrrb高表达产生类似于胚外内胚层干细胞的状态，其具有多潜能性；而Eomes的高表达则促进滋养外胚层的命运。

附：英文原文

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

Author: Hana Benchetrit, Mohammad Jaber, Valery Zayat, Oren Ram, Tommy Kaplan, Yosef Buganim

Issue&Volume:Jun 06, 2019 Volume 24Issue 6

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.

DOI: https://doi.org/10.1016/j.stem.2019.03.018

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30117-1