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Loss of endometrial plasticity in recurrent pregnancy loss

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Lucas, Emma S., Dyer, Nigel P., Murakami, Keisuke, Hou Lee, Yie, Chan, Yi-Wah, Grimaldi, Giulia, Muter, Joanne, Brighton, Paul (Paul J.), Moore, Jonathan D., Patel, Gnyaneshwari, Chan, Jerry K.Y., Takeda, Satoru, Lam, Eric W-F., Quenby, Siobhan, Ott, Sascha and Brosens, Jan J. (2016) Loss of endometrial plasticity in recurrent pregnancy loss. Stem Cells, 34 (2). pp. 346-356. doi:10.1002/stem.2222

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Official URL: http://dx.doi.org/10.1002/stem.2222

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Abstract

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.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
R Medicine > RG Gynecology and obstetrics
Divisions: Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Pregnancy , Pregnancy--Complications, Miscarriage , Stem cells
Journal or Publication Title: Stem Cells
Publisher: AlphaMed Press, Inc.
ISSN: 1066-5099
Official Date: 15 February 2016
Dates:
DateEvent
15 February 2016Available
4 September 2015Accepted
8 June 2015Submitted
Volume: 34
Number: 2
Page Range: pp. 346-356
DOI: 10.1002/stem.2222
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Funder: National Institute for Health Research (Great Britain). Biomedical Research Centre, Genesis Research Trust, University Hospitals Coventry and Warwickshire NHS Trust
Grant number: P16602 (Genesis Research Trust)

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