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

Rawlings, Thomas M. and Makwana, Komal and Taylor, Deborah M. and Molè, Matteo A. and Fishwick, Katherine J. and Tryfonos, Maria and Odendaal, Joshua and Hawkes, Amelia and Zernicka-Goetz, Magdalena and Hartshorne, Geraldine M. and Brosens, Jan J. and Lucas, Emma S. (2021) Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. eLife, 10 . Art. No. e69603. ISSN 2050-084X. PMCID PMC8523170. doi:10.7554/elife.69603. https://resolver.caltech.edu/CaltechAUTHORS:20211124-161127351

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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 characterized 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.7554/elife.69603DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523170PubMed CentralArticle
https://doi.org/10.1101/2021.03.02.433560DOIDiscussion Paper
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE168405Related ItemData
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE4888Related ItemData
ORCID:
AuthorORCID
Molè, Matteo A.0000-0001-7342-4849
Odendaal, Joshua0000-0001-7829-3729
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Brosens, Jan J.0000-0003-0116-9329
Lucas, Emma S.0000-0002-8571-8921
Additional Information:© 2021, Rawlings et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Preprint posted: March 2, 2021; 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). We are grateful to the women and couples who participated in this research. We are indebted to Dr. Siobhan Quenby and all the staff in the Centre for Reproductive Medicine and Biomedical Research Unit, University Hospitals Coventry and Warwickshire National Health Service Trust, for facilitating sample collection. This work was supported by a Wellcome Trust Investigator Award to JJB (212233/Z/18/Z). TMR was supported by the MRC Doctoral Training Partnership (MR/N014294/1) and a fellowship from Warwick-Wellcome Trust Translational Partnership initiative. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Author contributions: Thomas M Rawlings, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review and editing; Komal Makwana, Formal analysis, Investigation, Writing – review and editing; Deborah M Taylor, Joshua Odendaal, Amelia Hawkes, Geraldine M Hartshorne, Resources, Writing – review and editing; Matteo A Molè, Katherine J Fishwick, Maria Tryfonos, Investigation, Writing – review and editing; Magdalena Zernicka-Goetz, Supervision, Writing – review and editing; Jan J Brosens, Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review and editing; Emma S Lucas, Formal analysis, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review and editing. 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. Data availability: Single cell RNAseq data presented in this paper are openly available as a Gene Expression Omnibus DataSet (https://www.ncbi.nlm.nih.gov/gds) under accession number GSE168405. Other source data are presented in the Source Data tables as indicated in the corresponding Figure legends.
Funders:
Funding AgencyGrant Number
Wellcome Trust212233/Z/18/Z
Medical Research Council (UK)MR/N014294/1
Warwick-Wellcome TrustUNSPECIFIED
PubMed Central ID:PMC8523170
DOI:10.7554/elife.69603
Record Number:CaltechAUTHORS:20211124-161127351
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211124-161127351
Official Citation:Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. eLife 2021; 10:e69603. DOI: https://doi.org/10.7554/eLife.69603
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:112036
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Nov 2021 18:59
Last Modified:24 Nov 2021 18:59

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