Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids
- University of Warwick, United Kingdom
- University Hospitals Coventry and Warwickshire NHS Trust, United Kingdom
- 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.
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Single-cell RNA Sequencing of Endometrial Assembloid CulturesGene Expression Omnibus GSE168405.
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Molecular phenotyping of human endometriumGene Expression Omnibus GSE4888.
Article and author information
Author details
Magdalena Zernicka-Goetz
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.
Reviewing Editor
- Thomas E Spencer
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.
Version history
- Preprint posted: March 2, 2021 (view preprint)
- Received: April 20, 2021
- Accepted: September 3, 2021
- Accepted Manuscript published: September 6, 2021 (version 1)
- 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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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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