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

eLife

Matteo A Molè¹  Magdalena Zernicka-Goetz²  Katherine J Fishwick³  Thomas M Rawlings⁴  Komal Makwana⁴  Maria Tryfonos⁴  Emma S Lucas⁴  Geraldine M Hartshorne⁵  Deborah M Taylor⁵  Jan J Brosens⁶  Joshua Odendaal⁷  Amelia Hawkes⁷ 

[1] Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom;Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom;Synthetic Mouse and Human Embryology Group, California Institute of Technology (Caltech), Division of Biology and Biological Engineering, Pasadena, United Kingdom;Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Centre for Reproductive Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom;Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Centre for Early Life, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom;Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom;Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, United Kingdom;

关键词: endometrium;    embryo implantation;    organoid;    assembloid;    senescence;    decidualisation;    Human;   

DOI  :  10.7554/eLife.69603

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY