Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids
Authors
Rawlings, Thomas M
Makwana, Komal
Taylor, Deborah M
Molè, Matteo A
Fishwick, Katherine J
Tryfonos, Maria
Odendaal, Joshua
Hawkes, Amelia
Hartshorne, Geraldine M
Publication Date
2021-09-06Journal Title
eLife
Publisher
eLife Sciences Publications, Ltd
Volume
10
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Rawlings, T. M., Makwana, K., Taylor, D. M., Molè, M. A., Fishwick, K. J., Tryfonos, M., Odendaal, J., et al. (2021). Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. eLife, 10 https://doi.org/10.7554/elife.69603
Description
Funder: Warwick-Wellcome Trust Translational Partnership
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.
Keywords
Research Article, Cell Biology, endometrium, embryo implantation, organoid, assembloid, senescence, decidualisation, Human
Sponsorship
Wellcome Trust (212233/Z/18/Z)
MRC Doctoral Training Partnership (MR/N014294/1)
Identifiers
69603
External DOI: https://doi.org/10.7554/elife.69603
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329606
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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