Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids
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 charact...
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eLife Sciences Publications Ltd
2021
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oai:doaj.org-article:c6eb93a51cf149c9a1d9e132f792a02e2021-11-30T09:58:44ZModelling the impact of decidual senescence on embryo implantation in human endometrial assembloids10.7554/eLife.696032050-084Xe69603https://doaj.org/article/c6eb93a51cf149c9a1d9e132f792a02e2021-09-01T00:00:00Zhttps://elifesciences.org/articles/69603https://doaj.org/toc/2050-084XDecidual 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.Thomas M RawlingsKomal MakwanaDeborah M TaylorMatteo A MolèKatherine J FishwickMaria TryfonosJoshua OdendaalAmelia HawkesMagdalena Zernicka-GoetzGeraldine M HartshorneJan J BrosensEmma S LucaseLife Sciences Publications Ltdarticleendometriumembryo implantationorganoidassembloidsenescencedecidualisationMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
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endometrium embryo implantation organoid assembloid senescence decidualisation Medicine R Science Q Biology (General) QH301-705.5 |
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endometrium embryo implantation organoid assembloid senescence decidualisation Medicine R Science Q Biology (General) QH301-705.5 Thomas M Rawlings Komal Makwana Deborah M Taylor Matteo A Molè Katherine J Fishwick Maria Tryfonos Joshua Odendaal Amelia Hawkes Magdalena Zernicka-Goetz Geraldine M Hartshorne Jan J Brosens Emma S Lucas Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| description |
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. |
| format |
article |
| author |
Thomas M Rawlings Komal Makwana Deborah M Taylor Matteo A Molè Katherine J Fishwick Maria Tryfonos Joshua Odendaal Amelia Hawkes Magdalena Zernicka-Goetz Geraldine M Hartshorne Jan J Brosens Emma S Lucas |
| author_facet |
Thomas M Rawlings Komal Makwana Deborah M Taylor Matteo A Molè Katherine J Fishwick Maria Tryfonos Joshua Odendaal Amelia Hawkes Magdalena Zernicka-Goetz Geraldine M Hartshorne Jan J Brosens Emma S Lucas |
| author_sort |
Thomas M Rawlings |
| title |
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| title_short |
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| title_full |
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| title_fullStr |
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| title_full_unstemmed |
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| title_sort |
modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/c6eb93a51cf149c9a1d9e132f792a02e |
| work_keys_str_mv |
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| _version_ |
1718406709918040064 |