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Stem Cells. 2016 Feb;34(2):346-56. doi: 10.1002/stem.2222. Epub 2015 Dec 17.

Loss of Endometrial Plasticity in Recurrent Pregnancy Loss.

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Division of Reproductive Health, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry, England, United Kingdom.
Warwick Systems Biology Centre, University of Warwick, Coventry, England, United Kingdom.
Interdisciplinary Research Groups of BioSystems and Micromechanics, and Infectious Diseases, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
Department of Obstetrics and Gynaecology, Juntendo University Faculty of Medicine, Tokyo, Japan.
Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom.


Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure.


Decidualization; Endometrium; Epigenetics; High mobility group protein 2; Miscarriage; Pregnancy; Senescence; Stem cells

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