Stalling of the endometrial decidual reaction determines the recurrence risk of miscarriage
Brosens, Jan
Brosens, Jan
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Affiliation
1 Warwick Medical School, Division of Biomedical Sciences, University of Warwick; CV4 7AL Coventry, UK. 2 Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire National Health Service Trust; CV2 2DX Coventry, UK. 3 Research Group Genetics, Reproduction and Development, Vrije Universiteit Brussel; 1050 Brussels, Belgium. 4 Department of Clinical Immunology Service, University of Birmingham; B15 2TT Birmingham, UK. 5 Department of Cardiovascular Sciences, University of Leicester; LE1 7RH Leicester, UK. 6 Tommy's National Centre for Miscarriage Research, Imperial College London; W12 0HS. London, UK. *Corresponding author. Email: J.J.Brosens@warwick.ac.uk (J.J.B.) †These authors contributed equally to this work. ‡Present address: Lonza Pharma & Biotech; CB10 1XL Saffron Walden, UK. §Present address: Department of Obstetrics and Gynecology, Nagoya City University; 464- 8601 Nagoya, Japan. ¶Present address: School of Medicine and Population Health, University of Sheffield; S10 2RX, Sheffield, UK
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2025
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Abstract
In every menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an
inflammatory decidual reaction, rendering it poised for embryo implantation and
transformation into the decidua of pregnancy. Here, we show that the sequential functions of
the decidual reaction - implantation and decidualization - pivot on the time-sensitive loss of
progesterone-resistant DIO2+ stromal cells that form a specialized implantation niche and
reciprocal expansion of progesterone-dependent PLA2G2A+ pre-decidual cells.
Simultaneously, uterine natural killer (uNK) cell proliferation results in the accumulation of
immunotolerant subsets. Examination of endometrial biopsies from 924 women revealed that
the recurrence risk of miscarriage closely aligns with the incidence of a weakened or stalled
decidual reaction, more so than poor uNK cell expansion. Analysis of paired biopsies obtained
in different cycles and modeling in assembloids intimated that prior miscarriages disrupt
intercycle endometrial homeostasis and calibration of the decidual reaction. Our findings show
that erosion of the decidual reaction following a miscarriage drives the recurrence risk
irrespective of maternal age.
Citation
: Joanne Muter1,2 †, Chow-Seng Kong1 †,Mireia Taus Nebot1 ,Maria Tryfonos1,3 , Pavle Vrljicak1 ‡, Paul J. Brighton1 , Danai B. Dimakou4 , Megan Vickers1 , Hiroyuki Yoshihara1 §, Sascha Ott1 , Bee K. Tan5 , Phillip R. Bennett5 , Siobhan Quenby1,2, Alex Richter4 , Hilde Van de Velde3 , Emma S. Lucas1 ¶, Thomas M. Rawlings1 , and Jan J. Brosens1,2*
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Article