Transient chemical-mediated epigenetic modulation confers unrestricted lineage potential on human primed pluripotent stem cells  

作　　者：Shi Chen Yuanyuan He Lejun Lv Bei Liu Cheng Li Hongkui Deng Jun Xu 

机构地区：[1]Department of Cell Biology,School of Basic Medical Sciences,Peking University Stem Cell Research Center,Peking University Health Science Center,Peking University,Beijing,100191,China [2]Academy of Advanced Interdisciplinary Studies,Peking University,Beijing,100871,China [3]BeiCell Therapeutics,Beijing,100094,China [4]School of Life Sciences,Center for Bioinformatics,Center for Statistical Science,Peking University,Beijing,100871,China [5]MOE Engineering Research Center of Regenerative Medicine,School of Basic Medical Sciences,State Key Laboratory of Natural and Biomimetic Drugs,Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation,College of Life Sciences,Peking-Tsinghua Center for Life Sciences,Peking University,Beijing,100871,China

出　　处：《Science China(Life Sciences)》2025年第4期1084-1101,共18页中国科学(生命科学英文版)

基　　金：supported by the National Key Research and Development Program of China(2021YFA1100300);the National Natural Science Foundation of China(32288102,32370843 and 32025006)Part of the data analysis was performed on the High Performance Computing Platform of the Center for Life Sciences,Peking University。

摘　　要：Human primed pluripotent stem cells are capable of generating all the embryonic lineages.However,their extraembryonic trophectoderm potentials are limited.It remains unclear how to expand their developmental potential to trophectoderm lineages.Here we show that transient treatment with a cocktail of small molecule epigenetic modulators imparts trophectoderm lineage potentials to human primed pluripotent stem cells while preserving their embryonic potential.These chemically treated cells can generate trophectoderm-like cells and downstream trophoblast stem cells,diverging into syncytiotrophoblast and extravillous trophoblast lineages.Transcriptomic and CUT&Tag analyses reveal that these induced cells share transcriptional profiles with in vivo trophectoderm and cytotrophoblast,and exhibit reduced H3K27me3 modification at gene loci specific to trophoblast lineages compared with primed pluripotent cells.Mechanistic exploration highlighted the critical roles of epigenetic modulators HDAC2,EZH1/2,and KDM5s in the activation of trophoblast lineage potential.Our findings demonstrate that transient epigenetic resetting activates unrestricted lineage potential in human primed pluripotent stem cells,and offer new mechanistic insights into human trophoblast lineage specification and in vitro models for studying placental development and related disorders.

关 键 词：trophectoderm lineages human primed pluripotent stem cells epigenetic regulation small molecules 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]