Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids

  1. Thomas M Rawlings
  2. Komal Makwana
  3. Deborah M Taylor
  4. Matteo A Molè
  5. Katherine J Fishwick
  6. Maria Tryfonos
  7. Joshua Odendaal
  8. Amelia Hawkes
  9. Magdalena Zernicka-Goetz
  10. Geraldine M Hartshorne
  11. Jan Joris Brosens  Is a corresponding author
  12. Emma S Lucas
  1. University of Warwick, United Kingdom
  2. University Hospitals Coventry and Warwickshire NHS Trust, United Kingdom
  3. University of Cambridge, United Kingdom

Abstract

Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterised endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.

Data availability

Single cell RNAseq data presented in this paper are openly available as a Gene Expression Omnibus DataSet (www.ncbi.nlm.gov/gds) under accession number GSE168405. Other source data are presented in the Source Data tables as indicated in the corresponding Figure legends.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Thomas M Rawlings

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Komal Makwana

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Deborah M Taylor

    Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Matteo A Molè

    University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine J Fishwick

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Maria Tryfonos

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Joshua Odendaal

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Amelia Hawkes

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Magdalena Zernicka-Goetz

    Department of Physiology, Neuroscience and Development, University of Cambridge, Cambridgeshire, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7004-2471
  10. Geraldine M Hartshorne

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Jan Joris Brosens

    University of Warwick, Coventry, United Kingdom
    For correspondence
    J.J.Brosens@warwick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0116-9329
  12. Emma S Lucas

    University of Warwick, Coventry, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8571-8921

Funding

Wellcome Trust (212233/Z/18/Z)

  • Jan Joris Brosens

MRC Doctoral Training Partnership (MR/N014294/1)

  • Thomas M Rawlings

Warwick-Wellcome Trust Translational Partnership

  • Thomas M Rawlings

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Endometrial biopsies were obtained from women attending the Implantation Research Clinic, University Hospitals Coventry and Warwickshire National Health Service Trust. Written informed consent was obtained in accordance with the Declaration of Helsinki 2000. The study was approved by the NHS National Research Ethics Committee of Hammersmith and Queen Charlotte's Hospital NHS Trust (1997/5065) and Tommy's Reproductive Health Biobank (Project TSR19-002E, REC Reference: 18/WA/0356).The use of vitrified human blastocysts was carried out under a Human Fertilisation and Embryology Authority research licence (HFEA: R0155) with local National Health Service Research Ethics Committee approval (04/Q2802/26). Spare blastocysts were donated to research following informed consent by couples who had completed their fertility treatment at the Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire National Health Service Trust.

Reviewing Editor

  1. Thomas E Spencer

Publication history

  1. Preprint posted: March 2, 2021 (view preprint)
  2. Received: April 20, 2021
  3. Accepted: September 3, 2021
  4. Accepted Manuscript published: September 6, 2021 (version 1)
  5. Version of Record published: October 18, 2021 (version 2)

Copyright

© 2021, Rawlings et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Thomas M Rawlings
  2. Komal Makwana
  3. Deborah M Taylor
  4. Matteo A Molè
  5. Katherine J Fishwick
  6. Maria Tryfonos
  7. Joshua Odendaal
  8. Amelia Hawkes
  9. Magdalena Zernicka-Goetz
  10. Geraldine M Hartshorne
  11. Jan Joris Brosens
  12. Emma S Lucas
(2021)
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids
eLife 10:e69603.
https://doi.org/10.7554/eLife.69603

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