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Loss of Endometrial Plasticity in Recurrent Pregnancy Loss

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Title: Loss of Endometrial Plasticity in Recurrent Pregnancy Loss
Authors: Lucas, ES
Dyer, NP
Murakami, K
Hou Lee, Y
Chan, YW
Grimaldi, G
Muter, J
Brighton, PJ
Moore, JD
Patel, G
Chan, JKY
Takeda, S
Lam, EWF
Quenby, S
Ott, S
Brosens, JJ
Item Type: Journal Article
Abstract: © 2015 AlphaMed Press.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. Stem Cells 2016;34:346-356 Recurrent pregnancy loss is caused by endometrial stem cell deficiency, triggering heightened tissue senescence and impaired decidualization.
Issue Date: 17-Dec-2015
Date of Acceptance: 4-Sep-2015
URI: http://hdl.handle.net/10044/1/37426
DOI: http://dx.doi.org/10.1002/stem.2222
ISSN: 1066-5099
Publisher: Wiley
Start Page: 346
End Page: 356
Journal / Book Title: Stem Cells
Volume: 34
Issue: 2
Copyright Statement: © 2015 AlphaMed Press. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Sponsor/Funder: Imperial College Trust
Funder's Grant Number: N/A
Keywords: Immunology
06 Biological Sciences
10 Technology
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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