Loss of Endometrial Plasticity in Recurrent Pregnancy Loss. (17th December 2015)

• Record Type: Journal Article
• Authors: Lucas, Emma S.; Dyer, Nigel P.; Murakami, Keisuke; Hou Lee, Yie; Chan, Yi‐Wah; Grimaldi, Giulia; Muter, Joanne; Brighton, Paul J.; Moore, Jonathan D.; Patel, Gnyaneshwari; Chan, Jerry K.Y.; Takeda, Satoru; Lam, Eric W‐F.; Quenby, Siobhan; Ott, Sascha; Brosens, Jan J.
• Is Part Of: Stem cells. Volume 34:Number 2(2016:Feb.)
• Page Start: 346
• Page End: 356
• Publication Date: 2015-12-17
• Subjects: Epigenetics -- Stem cells -- Endometrium -- Pregnancy -- Miscarriage -- Decidualization -- Senescence -- High mobility group protein 2; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2222
• Languages: English
• ISSNs: 1066-5099

Abstract

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. Stem Cells 2016;34:346–356 Abstract : Recurrent pregnancy loss is caused by endometrial stem cell deficiency, triggering heightened tissue senescence and impaired decidualization.