Research in animals has shed light on how recurrent miscarriage is related to a dysregulation of the monthly "fertility window."
Jan Brosens (Warwick University, UK) and team demonstrated in mice that endometrial stromal cells induce a self-limiting auto-inflammatory response that controls the transient expression of uterine receptivity genes. They further demonstrate that the pro-inflammatory response in human endometrial stromal cells (HESCs) from women with recurrent pregnancy loss is disordered.
This may result in the fertility window remaining open for too long, and thus lead to embryos implanting out-of-phase into an environment that cannot support the pregnancy, ending in miscarriage.
Their research focused on the inflammatory response triggered by decidualization, the process that renders the endometrium transiently receptive to an implanting blastocyst, and the start of the 2-3 day period known as the fertility window, during which implantation is most likely to occur.
Brosens et al showed that during this inflammatory response, HESCs rapidly release interleukin-33 (IL-33), a key regulator of innate immune responses. In parallel, differentiating HESCs upregulate the IL-33 transmembrane receptor, ST2L, and other pro-inflammatory mediators, before mounting a profound anti-inflammatory response. This anti-inflammatory response includes downregulation of ST2L and increased expression of the soluble decoy receptor sST2.
The researchers also found that HESCs secreted factors permissive of embryo implantation in mice only during the pro-inflammatory phase of the decidual process. IL-33 knockdown in undifferentiated HESCs was sufficient to abrogate this pro-inflammatory decidual response, they note.
Furthermore, sequential activation of the IL-33/ST2L/sST2 axis was disordered in decidualizing HESCs taken from women with three or more recurrent pregnancy losses before 24 weeks' gestation. Signals from these cultures prolonged the implantation period, but caused subsequent pregnancy failure when introduced into mice.
"The study fundamentally changes our understanding of the issue with far reaching clinical implications. The IL-33/ST2 pathway is already considered to be a major target for therapeutic interventions across Alzheimer's, cardiovascular disease, obesity, asthma and other autoimmune disorders," commented co-author Siobhan Quenby, also from Warwick University, in a press statement.
"We believe that targeting the same pathway in the uterus may help to prevent miscarriage by regulating the fertility window. It's an exciting discovery that we hope will mean new developments for a group of women for who there isn't currently any help."
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