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
SIGNIFICANCE STATEMENTRecurrent 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.
Luminol is a presumptive test reagent used for the location of latent bloodstains. Various formulations are used by different forensic practitioners and commercial products are also widely available. There is little concurrence between authors with regards to the sensitivity limits of luminol which can vary significantly depending upon the substrate. We evaluated the sensitivity and stability of five different luminol formulations on a range of blood dilutions. All formulations showed an overall decrease in performance over 24 h though the effect was more gradual on a non-porous surface compared to porous. We found that BlueStar® Magnum showed the greatest sensitivity compared to other formulations and detected 50 μl of 1/100,000 blood dilutions on both porous and non-porous surfaces. Two formulations of luminol were selected based on the result of the sensitivity and stability study and were assessed for their impact on the DNA profiling process. There was a statistically significant improvement in DNA profile peak area from luminol-treated samples when compared to control samples of neat blood stains. However, at the weaker blood dilution of 1/1,000, the difference between control and luminol-treated samples was dependent on the substrate type with porous (fabric) samples showing a significant difference and non-porous (tile) swabbed samples requiring further work to conclusively ascertain the effect.
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