Epiblast inducers capture mouse trophectoderm stem cells in vitro and pattern blastoids for implantation in utero

Jinwoo Seong, Javier Frias-Aldeguer, Viktoria Holzmann, Harunobu Kagawa, Giovanni Sestini, Heidar Heidari Khoei, Yvonne Scholte Op Reimer, Maarten Kip, Saurabh J. Pradhan, Lucas Verwegen, Judith Vivié, Linfeng Li, Anna Alemany, Jeroen Korving, Frank Darmis, Alexander van Oudenaarden, Derk ten Berge, Niels Geijsen, Nicolas C. Rivron*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

The embryo instructs the allocation of cell states to spatially regulate functions. In the blastocyst, patterning of trophoblast (TR) cells ensures successful implantation and placental development. Here, we defined an optimal set of molecules secreted by the epiblast (inducers) that captures in vitro stable, highly self-renewing mouse trophectoderm stem cells (TESCs) resembling the blastocyst stage. When exposed to suboptimal inducers, these stem cells fluctuate to form interconvertible subpopulations with reduced self-renewal and facilitated differentiation, resembling peri-implantation cells, known as TR stem cells (TSCs). TESCs have enhanced capacity to form blastoids that implant more efficiently in utero due to inducers maintaining not only local TR proliferation and self-renewal, but also WNT6/7B secretion that stimulates uterine decidualization. Overall, the epiblast maintains sustained growth and decidualization potential of abutting TR cells, while, as known, distancing imposed by the blastocyst cavity differentiates TR cells for uterus adhesion, thus patterning the essential functions of implantation.

Original languageEnglish
Pages (from-to)1102-1118.e8
JournalCell Stem Cell
Volume29
Issue number7
DOIs
Publication statusPublished - 7 Jul 2022

Bibliographical note

Funding Information:
We would like to thank J. Deschamps for providing the CDX2-eGFP mice; A. Barve for preliminary data analysis; S. van der Elst and R. van der linden for helping with FACS assays; A. de Graaf for helping with microscopy; H. Begthel for helping with histology; H.C. Theussl for helping with both TSC injection into morula and uterine transfer of chimeric blastocysts; and all mouse caretaking staff, especially J. Patry, for their help. N.C.R. is supported by an ERC Consolidator grant (2020 ERC-CoG no. 101002317-BLASTOID). J.S. is supported by the European Union's Framework Program for Research and Innovation Horizon 2020 (2014–2020) under the Marie Curie Skłodowska Grant Agreement no. 847548. V.H. is supported by a Boehringer Ingelheim Fonds Fellowship. H.H.K. is supported by the Austrian Science Fund (FWF), Lise Meitner Program M3131-B. H.K. is supported by the Japan Society for the Promotion of Science Overseas Research Fellowships. G.S. is supported by the HFSP number RGY0081/2019. S.P. is supported by the VIP2 program that has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 847548. Conceptualization: J.S. J.F.A. V.H. H.K. and N.C.R.; formal analysis: J.S. J.F.A. V.H. G.S. A.A. and N.C.R; funding acquisition: J.S. V.H. and N.C.R.; investigation: J.S. J.F.A. V.H. H.K. H.H.K. Y.S.R.O. L.V. J.V. L.L. J.K. F.D. and A.v.O.; methodology: J.S. V.H. H.K. H.H.K. and M.K.; validation: J.S. and V.H.; visualization: J.S. J.F.A. and V.H.; writing – original draft: J.S. J.F.A. V.H. and N.C.R.; writing – review & editing: J.S. V.H. H.K. D.t.B. and N.C.R.; project administration: N.C.R.; supervision: N.C.R. N.C.R. and N.G. are inventors on a patent (EP2986711)filed on 2013-04-16 in the Netherlands, currently maintained by the IMBA in Austria, and entitled, “Blastoid, cell line based artificial blastocyst.”, We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Funding Information:
We would like to thank J. Deschamps for providing the CDX2-eGFP mice; A. Barve for preliminary data analysis; S. van der Elst and R. van der linden for helping with FACS assays; A. de Graaf for helping with microscopy; H. Begthel for helping with histology; H.C. Theussl for helping with both TSC injection into morula and uterine transfer of chimeric blastocysts; and all mouse caretaking staff, especially J. Patry, for their help. N.C.R. is supported by an ERC Consolidator grant (2020 ERC-CoG no. 101002317-BLASTOID). J.S. is supported by the European Union’s Framework Program for Research and Innovation Horizon 2020 (2014–2020) under the Marie Curie Skłodowska Grant Agreement no. 847548 . V.H. is supported by a Boehringer Ingelheim Fonds Fellowship. H.H.K. is supported by the Austrian Science Fund ( FWF ), Lise Meitner Program M3131-B. H.K. is supported by the Japan Society for the Promotion of Science Overseas Research Fellowships. G.S. is supported by the HFSP number RGY0081/2019 . S.P. is supported by the VIP2 program that has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 847548 .

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© 2022 Elsevier Inc.

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