Skip to main content

Advertisement

Log in

Here and there a trophoblast, a transcriptional evaluation of trophoblast cell models

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

A recent explosion of methods to produce human trophoblast and stem cells (hTSCs) is fuelling a renewed interest in this tissue. The trophoblast is critical to reproduction by facilitating implantation, maternal physiological adaptations to pregnancy and the growth of the fetus through transport of nutrients between the mother and fetus. More broadly, the trophoblast has phenotypic properties that make it of interest to other fields. Its angiogenic and invasive properties are similar to tumours and could identify novel drug targets, and its ability to regulate immunological tolerance of the allogenic fetus could lead to improvements in transplantations. Within this review, we integrate and assess transcriptomic data of cell-based models of hTSC alongside in vivo samples to identify the utility and applicability of these models. We also integrate single-cell RNA sequencing data sets of human blastoids, stem cells and embryos to identify how these models may recapitulate early trophoblast development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Availability of data and material

Please see Supplemental Tables 1 and 2 for lists of accession IDs for data sets and specific samples used in this analysis.

References

  1. Shi Y, Inoue H, Wu JC, Yamanaka S (2017) Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov 16:115–130. https://doi.org/10.1038/nrd.2016.245

    Article  CAS  Google Scholar 

  2. Aghazadeh Y, Poon F, Sarangi F et al (2021) Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models. Cell Stem Cell 28:1936-1949.e8. https://doi.org/10.1016/j.stem.2021.08.001

    Article  CAS  Google Scholar 

  3. Mercuri ND, Cox BJ (2021) Meta-research: a poor research landscape hinders the progression of knowledge and treatment of reproductive diseases. bioRxiv 2021.11.16.468787. https://doi.org/10.1101/2021.11.16.468787

  4. Tanaka S, Kunath T, Hadjantonakisa K et al (1998) Promotion of trophoblast stem cell proliferation by FGF4. Science 282:2072–2075

    Article  CAS  Google Scholar 

  5. Kunath T, Yamanaka Y, Detmar J et al (2014) Developmental differences in the expression of FGF receptors between human and mouse embryos. Placenta 35:1079–1088. https://doi.org/10.1016/j.placenta.2014.09.008

    Article  CAS  Google Scholar 

  6. Okae H, Toh H, Sato T et al (2018) Derivation of human trophoblast stem cells. Cell Stem Cell 22:50-63.e6. https://doi.org/10.1016/j.stem.2017.11.004

    Article  CAS  Google Scholar 

  7. Sheridan MA, Fernando RC, Gardner L et al (2020) Establishment and differentiation of long-term trophoblast organoid cultures from the human placenta. Nat Protoc 15:3441–3463. https://doi.org/10.1038/s41596-020-0381-x

    Article  CAS  Google Scholar 

  8. Haider S, Meinhardt G, Saleh L et al (2018) Self-Renewing trophoblast organoids recapitulate the developmental program of the early human placenta. Stem Cell Rep. https://doi.org/10.1016/j.stemcr.2018.07.004

    Article  Google Scholar 

  9. Xu R-H, Chen X, Li DS et al (2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 20:1261–1264. https://doi.org/10.1038/nbt761

    Article  CAS  Google Scholar 

  10. Amita M, Adachi K, Alexenkoa P et al (2013) Complete and unidirectional conversion of human embryonic stem cells to trophoblast by BMP4. Proc Natl Acad Sci. https://doi.org/10.1073/pnas.1303094110

    Article  Google Scholar 

  11. Krendl C, Shaposhnikov D, Rishko V et al (2017) GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency. Proc Natl Acad Sci 114:E9579–E9588. https://doi.org/10.1073/pnas.1708341114

    Article  CAS  Google Scholar 

  12. Li Y, Moretto-Zita M, Soncin F et al (2013) BMP4-directed trophoblast differentiation of human embryonic stem cells is mediated through a ΔNp63+ cytotrophoblast stem cell state. Development 140:3965–3976. https://doi.org/10.1242/dev.092155

    Article  CAS  Google Scholar 

  13. Bernardo ASASAS, Faial T, Gardner L et al (2011) BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. Cell Stem Cell 9:144–155. https://doi.org/10.1016/j.stem.2011.06.015

    Article  CAS  Google Scholar 

  14. Roberts RM, Loh KM, Amita M et al (2014) Differentiation of trophoblast cells from human embryonic stem cells: to be or not to be? Reproduction 147:D1-12. https://doi.org/10.1530/REP-14-0080

    Article  CAS  Google Scholar 

  15. Zheng Y, Xue X, Shao Y et al (2019) Controlled modelling of human epiblast and amnion development using stem cells. Nature 573:421–425. https://doi.org/10.1038/s41586-019-1535-2

    Article  CAS  Google Scholar 

  16. Hayashi Y, Furue MK, Tanaka S et al (2010) BMP4 induction of trophoblast from mouse embryonic stem cells in defined culture conditions on laminin. In Vitro Cell Dev Biol Anim 46:416–430. https://doi.org/10.1007/s11626-009-9266-6

    Article  CAS  Google Scholar 

  17. Harun R, Ruban L, Matin M et al (2006) Cytotrophoblast stem cell lines derived from human embryonic stem cells and their capacity to mimic invasive implantation events. Hum Reprod 21:1349–1358. https://doi.org/10.1093/humrep/del017

    Article  CAS  Google Scholar 

  18. Theunissen TW, Friedli M, He Y et al (2016) Molecular criteria for defining the naive human pluripotent state resource molecular criteria for defining the naive human pluripotent state. Cell Stem Cell 19(4):502–515

    Article  CAS  Google Scholar 

  19. Cinkornpumin JK, Kwon SY, Guo Y et al (2020) Naive human embryonic stem cells can give rise to cells with a trophoblast-like transcriptome and methylome. Stem Cell Rep 15:198–213. https://doi.org/10.1016/j.stemcr.2020.06.003

    Article  CAS  Google Scholar 

  20. Dong C, Beltcheva M, Gontarz P et al (2020) Derivation of trophoblast stem cells from naïve human pluripotent stem cells. Elife 9:1–26. https://doi.org/10.7554/eLife.52504

    Article  Google Scholar 

  21. Liu X, Ouyang JF, Rossello FJ et al (2020) Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature 586:101–107. https://doi.org/10.1038/s41586-020-2734-6

    Article  CAS  Google Scholar 

  22. Li R, Zhong C, Yu Y et al (2019) Generation of blastocyst-like structures from mouse embryonic and adult cell cultures. Cell 179:687-702.e18. https://doi.org/10.1016/j.cell.2019.09.029

    Article  CAS  Google Scholar 

  23. Yanagida A, Spindlow D, Nichols J et al (2021) Naive stem cell blastocyst model captures human embryo lineage segregation. Cell Stem Cell 28:1016-1022.e4. https://doi.org/10.1016/j.stem.2021.04.031

    Article  CAS  Google Scholar 

  24. Yu L, Wei Y, Duan J, Schmitz DA, Sakurai M, Wang L, Wang K, Zhao S, Hon GC, Wu J (2021) Blastocyst-like structures generated from human pluripotent stem cells. Nature 591(7851):620–626

    Article  CAS  Google Scholar 

  25. Kagawa H, Javali A, Khoei HH et al (2022) Human blastoids model blastocyst development and implantation. Nature 601:600–605. https://doi.org/10.1038/s41586-021-04267-8

    Article  CAS  Google Scholar 

  26. McInnes L, Healy J, Melville J (2018) UMAP: uniform manifold approximation and projection for dimension reduction. J Open Source Softw 3:861

    Article  Google Scholar 

  27. Zygmunt M, Herr F, Münstedt K et al (2003) Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 110:10–18. https://doi.org/10.1016/S0301-2115(03)00168-4

    Article  CAS  Google Scholar 

  28. Christiansen OB (2013) Reproductive immunology. Mol Immunol 55:8–15. https://doi.org/10.1016/j.molimm.2012.08.025

    Article  CAS  Google Scholar 

  29. Carter AM (2012) Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses. Physiol Rev 92:1543–1576. https://doi.org/10.1152/physrev.00040.2011

    Article  CAS  Google Scholar 

  30. Soncin F, Natale D, Parast MM (2014) Signaling pathways in mouse and human trophoblast differentiation: a comparative review. Cell Mol Life Sci 72:1291–1302. https://doi.org/10.1007/s00018-014-1794-x

    Article  CAS  Google Scholar 

  31. Knöfler M, Pollheimer J (2013) Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling. Front Genet 4:190. https://doi.org/10.3389/fgene.2013.00190

    Article  CAS  Google Scholar 

  32. Doherty KR, Cave A, Davis DB et al (2005) Normal myoblast fusion requires myoferlin. Development 132:5565–5575. https://doi.org/10.1242/dev.02155

    Article  CAS  Google Scholar 

  33. Robinson JM, Ackerman WE, Behrendt NJ, Vandre DD (2009) While dysferlin and myoferlin are coexpressed in the human placenta, only dysferlin expression is responsive to trophoblast fusion in model systems. Biol Reprod 81:33–39. https://doi.org/10.1095/biolreprod.108.074591

    Article  CAS  Google Scholar 

  34. Petropoulos S, Deng Q, Panula SP et al (2016) Single-cell RNA-seq reveals lineage and X-chromosome dynamics in human preimplantation embryos. Cell 165:1012–1026

    Article  CAS  Google Scholar 

  35. Tonge PD, Corso AJ, Monetti C et al (2014) Divergent reprogramming routes lead to alternative stem-cell states. Nature 516:192–197. https://doi.org/10.1038/nature14047

    Article  CAS  Google Scholar 

  36. Lee CQEE, Gardner L, Turco M et al (2016) What Is trophoblast? A combination of criteria define human first-trimester trophoblast. Stem Cell Rep 6:257–272. https://doi.org/10.1016/j.stemcr.2016.01.006

    Article  CAS  Google Scholar 

  37. Posfai E, Schell JP, Janiszewski A et al (2021) Evaluating totipotency using criteria of increasing stringency. Nat Cell Biol 23:49–60. https://doi.org/10.1038/s41556-020-00609-2

    Article  CAS  Google Scholar 

  38. Maherali N, Hochedlinger K (2008) Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 3:595–605. https://doi.org/10.1016/j.stem.2008.11.008

    Article  CAS  Google Scholar 

  39. Hussein SMI, Elbaz J, Nagy AA (2013) Genome damage in induced pluripotent stem cells: assessing the mechanisms and their consequences. Bioessays 35:152–162. https://doi.org/10.1002/bies.201200114

    Article  CAS  Google Scholar 

  40. Knox K, Baker JC (2008) Genomic evolution of the placenta using co-option and duplication and divergence. Genome Res 18:695–705. https://doi.org/10.1101/gr.071407.107

    Article  CAS  Google Scholar 

  41. Yu L, Wei Y, Duan J et al (2021) Blastocyst-like structures generated from human pluripotent stem cells. Springer, USA

    Book  Google Scholar 

  42. Sakoff JA, Murdoch RN (1993) Cell Reaction in pseudopregnant mice. J Reprod Fertil 101:91–102

    Google Scholar 

  43. Paria BC, Ma WG, Tan J et al (2001) Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci USA 98:1047–1052. https://doi.org/10.1073/pnas.98.3.1047

    Article  CAS  Google Scholar 

  44. Io S, Kabata M, Iemura Y et al (2021) Capturing human trophoblast development with naive pluripotent stem cells in vitro. Cell Stem Cell 28:1023-1039.e13. https://doi.org/10.1016/j.stem.2021.03.013

    Article  CAS  Google Scholar 

  45. Guo G, Stirparo GG, Strawbridge SE et al (2021) Human naive epiblast cells possess unrestricted lineage potential. Cell Stem Cell 28:1040-1056.e6. https://doi.org/10.1016/j.stem.2021.02.025

    Article  CAS  Google Scholar 

  46. Mischler A, Karakis V, Mahinthakumar J et al (2021) Two distinct trophectoderm lineage stem cells from human pluripotent stem cells. J Biol Chem 296:100386. https://doi.org/10.1016/j.jbc.2021.100386

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Frances Wong for assistance with the integration of processing RNA sequencing data.

Funding

BC is supported in part by a Tier II Canada Research Chair in maternal–fetal medicine. KN was supported in part by the Undergraduate Research Opportunity Fund from the Department of Physiology at the University of Toronto.

Author information

Authors and Affiliations

Authors

Contributions

BC conceived the project. KN and BC analyzed data, generated figures and tables and wrote the manuscript.

Corresponding author

Correspondence to Brian J. Cox.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest. The funding agencies played no role in the direction of the research.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agreed to the manuscript and conclusions.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 Supplemental Table 1. List of all studies used in the analysis (CSV 0 KB)

Supplementary file2 Supplemental Table 2. List of all samples used in the analysis (XLSX 22 KB)

18_2022_4589_MOESM3_ESM.xlsx

Supplementary file3 Supplemental Table 3. Enrichment Map Ontologies for terminal clusters 0, 2, 3 and 5. Ontologies are based on the word frequency of nodes with significant overlap in gene members. All nodes were significant at an FDR corrected p-values of <0.1 (XLSX 12 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cox, B.J., Naismith, K. Here and there a trophoblast, a transcriptional evaluation of trophoblast cell models. Cell. Mol. Life Sci. 79, 584 (2022). https://doi.org/10.1007/s00018-022-04589-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04589-4

Keywords

Navigation