ISRIB facilitates the co‐culture of human trophoblast stem cells and embryonic stem cells

Author:

Xia Shuwei1234,Yu Dainan1234,Wang Yue1234,He Beijia1234,Rong Yin1234,Chen Shuo1234,Xiao Zhenyu1235,Wang Hongmei1234ORCID,Wu Hao123,Yan Long123ORCID

Affiliation:

1. Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology, Chinese Academy of Sciences Beijing China

2. Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing China

3. Beijing Institute for Stem Cell and Regenerative Medicine Beijing China

4. University of Chinese Academy of Sciences Beijing China

5. School of Life Science Beijing Institute of Technology Beijing China

Abstract

AbstractThe embryo‐like structures (embryoids) constructed by aggregating embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) have provided revolutionary tools for studying the intricate interaction between embryonic and extra‐embryonic tissues during early embryonic development, which has been achieved in mice. However, due to the opposite dependence on some signalling pathways for in vitro culture of human ESCs (hESCs) and TSCs (hTSCs), particularly WNT and TGFβ signalling pathways, which limits the construction of human post‐implantation embryoids by aggregating hESCs and hTSCs. To overcome this challenge, here, by screening 1639 chemicals, we found that an inhibitor of integrated stress response, ISRIB, can replace WNT agonists and TGFβ inhibitors to maintain the stemness and differentiation capacity of hTSCs. Thus, we developed an ISRIB‐dependent in vitro culture medium for hTSCs, namely nTSM. Furthermore, we demonstrated that ISRIB could also maintain the hESC stemness. Using a 3D co‐culture system (hESCs and hTSCs aggregate, ETA), we demonstrated that a 1:1 mixture of hESC culture medium (ESM) and nTSM improved the cell proliferation and organisation of both hESC‐ and hTSC‐compartments and the lumenogenesis of hESC‐compartment in ETAs. Overall, our study provided an ISRIB‐dependent system for co‐culturing hESCs and hTSCs, which facilitated the construction of human embryoids by aggregating hESCs and hTSCs.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Beijing Municipal Natural Science Foundation

Publisher

Wiley

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