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

doi:10.1016/j.stem.2022.06.002

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 journal › Article › Academic › peer-review

2 Citations (Scopus)

45 Downloads (Pure)

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 language	English
Pages (from-to)	1102-1118.e8
Journal	Cell stem cell
Volume	29
Issue number	7
DOIs	https://doi.org/10.1016/j.stem.2022.06.002
Publication status	Published - 7 Jul 2022

Keywords

blastocyst
blastoid
induction
trophoblast stem cells
trophectoderm stem cells
trophectoderm
implantation
decidualization

Access to Document

10.1016/j.stem.2022.06.002Licence: CC BY

1-s2.0-S193459092200251X-mainFinal published version, 5.79 MBLicence: CC BY

Cite this

Seong, J., Frias-Aldeguer, J., Holzmann, V., Kagawa, H., Sestini, G., Heidari Khoei, H., Scholte Op Reimer, Y., Kip, M., Pradhan, S. J., Verwegen, L., Vivié, J., Li, L., Alemany, A., Korving, J., Darmis, F., van Oudenaarden, A., ten Berge, D., Geijsen, N., & Rivron, N. C. (2022). Epiblast inducers capture mouse trophectoderm stem cells in vitro and pattern blastoids for implantation in utero. Cell stem cell, 29(7), 1102-1118.e8. https://doi.org/10.1016/j.stem.2022.06.002

@article{f8a9686f09dd4248857f9acdd6f0cf6e,

title = "Epiblast inducers capture mouse trophectoderm stem cells in vitro and pattern blastoids for implantation in utero",

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.",

keywords = "blastocyst, blastoid, induction, trophoblast stem cells, trophectoderm stem cells, trophectoderm, implantation, decidualization",

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

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 Sk{\l}odowska 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 Sk{\l}odowska-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{\textquoteright}s Framework Program for Research and Innovation Horizon 2020 (2014–2020) under the Marie Curie Sk{\l}odowska 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{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 847548 . Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = jul,

day = "7",

doi = "10.1016/j.stem.2022.06.002",

language = "English",

volume = "29",

pages = "1102--1118.e8",

journal = "Cell stem cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "7",

}

Seong, J, Frias-Aldeguer, J, Holzmann, V, Kagawa, H, Sestini, G, Heidari Khoei, H, Scholte Op Reimer, Y, Kip, M, Pradhan, SJ, Verwegen, L, Vivié, J, Li, L, Alemany, A, Korving, J, Darmis, F, van Oudenaarden, A, ten Berge, D, Geijsen, N & Rivron, NC 2022, 'Epiblast inducers capture mouse trophectoderm stem cells in vitro and pattern blastoids for implantation in utero', Cell stem cell, vol. 29, no. 7, pp. 1102-1118.e8. https://doi.org/10.1016/j.stem.2022.06.002

TY - JOUR

T1 - Epiblast inducers capture mouse trophectoderm stem cells in vitro and pattern blastoids for implantation in utero

AU - Seong, Jinwoo

AU - Frias-Aldeguer, Javier

AU - Holzmann, Viktoria

AU - Kagawa, Harunobu

AU - Sestini, Giovanni

AU - Heidari Khoei, Heidar

AU - Scholte Op Reimer, Yvonne

AU - Kip, Maarten

AU - Pradhan, Saurabh J.

AU - Verwegen, Lucas

AU - Vivié, Judith

AU - Li, Linfeng

AU - Alemany, Anna

AU - Korving, Jeroen

AU - Darmis, Frank

AU - van Oudenaarden, Alexander

AU - ten Berge, Derk

AU - Geijsen, Niels

AU - Rivron, Nicolas C.

N1 - 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 . Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/7/7

Y1 - 2022/7/7

N2 - 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.

AB - 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.

KW - blastocyst

KW - blastoid

KW - induction

KW - trophoblast stem cells

KW - trophectoderm stem cells

KW - trophectoderm

KW - implantation

KW - decidualization

UR - http://www.scopus.com/inward/record.url?scp=85133494543&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2022.06.002

DO - 10.1016/j.stem.2022.06.002

M3 - Article

C2 - 35803228

AN - SCOPUS:85133494543

SN - 1934-5909

VL - 29

SP - 1102-1118.e8

JO - Cell stem cell

JF - Cell stem cell

IS - 7

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this