Loss of Endometrial Plasticity in Recurrent Pregnancy Loss (Feb 2016)

Loss of Endometrial Plasticity in Recurrent Pregnancy Loss
Stem Cells, Volume 34, Issue 2 February 2016
Lucas ES1, Dyer NP2, Murakami K1, Lee YH3, Chan YW2, Grimaldi G1, Muter J1, Brighton PJ1, Moore JD2, Patel G1, Chan JK4, Takeda S5, Lam EW6, Quenby S1, Ott S2, Brosens JJ1.
Author(s) affiliation:
1Division of Reproductive Health, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry, England, United Kingdom.
2Warwick Systems Biology Centre, University of Warwick, Coventry, England, United Kingdom.
3Interdisciplinary Research Groups of BioSystems and Micromechanics, and Infectious Diseases, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
4Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
5Department of Obstetrics and Gynaecology, Juntendo University Faculty of Medicine, Tokyo, Japan.
6Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom.


Short description:
Recurrent pregnancy loss (RPL) is a common and distressing disorder. While many risk factors have been invoked to explain RPL, the underlying pathological pathways are not understood. We demonstrate that RPL is strongly associated with uterine stem cell deficiency and enhanced cellular senescence. This in turn perturbs endometrial preparation for pregnancy, a process termed decidualization, and persistence of these defects over several conception cycles will lead to consecutive miscarriages. Our findings open up new avenues to screen women prior to pregnancy for the risk of miscarriage and point to the potential of cell-based therapies in the prevention of RPL.
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Abstract taken from PubMed

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.
Link to the paper on PubMed


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