Biology subjects

Massri, N.

Publications and source records attributed to Massri, N..

4 recordsLinked to original sources

bioRxiv2025

Murine implantation chamber formation precedes natural and artificial decidualization

During pregnancy uterine stromal cells undergo a mesenchymal to epithelial cell transition termed decidualization. In humans initiation of decidualization occurs in the absence of an embryo resulting in a need to identify embryo-independent molecular cues that can initiate decidualization. Although, similar to humans, decidualization in the mouse can be induced in the absence of an embryo, whether an implantation event is prerequisite for such decidualization is not known. In this study using different models of estrogen-dependent implantation, including natural (embryo) and artificial (sesame oil, agarose only beads, and Concanavalin A coated agarose beads) we determined that implantation chamber formation precedes decidualization. We show that focal stimuli, including the embryo, Concanavalin A coated bead, and oil droplets, induce V-shaped implantation chambers that lead to sub-epithelial PTGS2 expression and decidualization. Unfertilized eggs and uncoated agarose blue beads fail to form an implantation chamber and do not initiate decidualization. Further, we show that lectins that share sugar binding properties with Concanavalin A can also induce a V-shaped implantation chamber. Finally, using second harmonic generation we show that during decidualization collagen fibers spread radially away from the implantation chamber irrespective of the focal signal used for inducing the chamber. Thus, in the mouse artificial decidualization also initiates at the site of implantation chamber formation. These findings are critical when separating physical stimulus-dependent, embryo-dependent and embryo-independent mechanisms of decidualization that underlie a successful pregnancy.

developmental biology↗

bioRxiv2025

Pre-implantation non-steroidal anti-inflammatory drug treatment disrupts mouse embryo spacing and post-implantation chamber morphogenesis

Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the prostaglandin synthase (PTGS) enzymes PTGS1 and PTGS2, may present a risk when consumed during early pregnancy. The impact of PTGS enzyme inhibition by NSAIDS on the three-dimensional organization and function of uterine compartments in context of implantation success is not well known. Here we show that pre-implantation treatment of mouse pregnancy with indomethacin, an NSAID that inhibits both PTGS1 and PTGS2, results in embryo crowding, delayed embryo implantation, defective implantation chamber formation that eventually results in significant pregnancy loss. These effects are dose dependent as lower doses of indomethacin do not show these effects on pregnancy. When embryo spacing defects were observed, a significant proportion of embryos that showed delayed growth or resorption were located in distinct decidual sites, suggesting that additional mechanisms beyond spatial distribution are at play. These findings highlight the potential risks associated with NSAID use during early pregnancy and underscore the need for further research into the underlying molecular mechanisms and the development of safer pain management strategies during pregnancy.

physiology↗

bioRxiv2024

Uterine stromal but not epithelial PTGS2 is critical for murine pregnancy success

Use of non-steroidal anti-inflammatory drugs that target prostaglandin synthase (PTGS) enzymes have been implicated in miscarriage. Further, PTGS2-derived prostaglandins are reduced in the endometrium of patients with a history of implantation failure. However, in the mouse model of pregnancy, peri-implantation PTGS2 function is controversial. Some studies suggest that Ptgs2-/- mice display deficits in ovulation, fertilization, and implantation, while other studies suggest a role for PTGS2 only in ovulation but not implantation. Further, the uterine cell type responsible for PTGS2 function and role of PTGS2 in regulating implantation chamber formation is not known. To address this we generated tissue-specific deletion models of Ptgs2. We observed that PTGS2 ablation from the epithelium alone in Ltfcre/+; Ptgs2f/f mice and in both the epithelium and endothelium of the Pax2cre/+; Ptgs2f/f mice does not affect embryo implantation. Further, deletion of PTGS2 in the ovary, oviduct, and the uterus using Pgrcre/+; Ptgs2f/f does not disrupt pre-implantation events but instead interferes with post-implantation chamber formation, vascular remodeling and decidualization. While all embryos initiate chamber formation, more than half of the embryos fail to transition from blastocyst to epiblast stage, resulting in embryo death and resorbing decidual sites at mid-gestation. Thus, our results suggest no role for uterine epithelial PTGS2 in early pregnancy but instead highlight a role for uterine stromal PTGS2 in modulating post-implantation embryo and implantation chamber growth. Overall, our study provides clarity on the compartment-specific role of PTGS2 and provides a valuable model for further investigating the role of stromal PTGS2 in post-implantation embryo development.

developmental biology↗

bioRxiv2024

Yes Associated Transcriptional Regulator 1 (YAP1) and WW Domain Containing Transcription Regulator (WWTR1) are required for murine pregnancy initiation

Endometrial stromal cell decidualization is required for pregnancy success. Although this process is integral to fertility, many of the intricate molecular mechanisms contributing to decidualization remain undefined. One pathway that has been implicated in endometrial stromal cell decidualization in humans in vitro is the Hippo signaling pathway. Two previously conducted studies showed that the effectors of the Hippo signaling pathway, YAP1 and WWTR1, were required for decidualization of primary stromal cells in culture. To investigate the in vivo role of YAP1 and WWTR1 in decidualization and pregnancy initiation, we generated a Progesterone Cre mediated partial double knockout (pdKO) of Yap1 and Wwtr1. Female pdKOs exhibited subfertility, a compromised decidualization response, partial interruption in embryo transport, blunted endometrial receptivity, delayed implantation and subsequent embryonic development, and a unique transcriptional profile. Bulk mRNA sequencing revealed aberrant maternal remodeling evidenced by significant alterations in extracellular matrix proteins at 7.5 days post-coitus in pdKO dams and enrichment for terms associated with fertility-compromising diseases like pre-eclampsia and endometriosis. Our results indicate a required role for YAP1 and WWTR1 for successful mammalian uterine function and pregnancy success.

molecular biology↗