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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
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 |
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| 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: |
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| 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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