Uterine receptivity and uterus-embryo interactions, strategies to regulate implantation and improve IVF success rates

Uterine receptivity and uterus-embryo interactions, strategies to regulate implantation and improve IVF success rates is a Research Project for the Archived: Implantation and Placental Development Research Group, under the Centre for Reproductive Health.

Project Leader

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Embryo implantation is essential to initiate pregnancy. It requires two entirely different process to develop synchronously: first, an implantation-competent embryo must develop, and second, the uterus must become receptive to the embryo so that it can implant. Failure to establish receptivity or an inappropriate interaction between the uterus and the embryo causes implantation failure. The success of embryo implantation is a critical limiting factor in IVF treatment. At present, there is no simple way to determine whether a woman’s uterus is ready for implantation. Our work focuses on discovering diagnostic strategies to predict when the uterus is receptive and which embryos are most likely to achieve successful implantation during IVF.

The underlying mechanisms governing the establishment of human uterine receptivity remain largely unknown. Our research aims to uncover these molecular mechanisms, and to understand the fundamental cell biology of uterine preparation for receptivity and uterus-embryo interaction for implantation.

In particular, our group is interested in the luminal uterine epithelium, which makes the first contact with the embryo prior to the establishment of pregnancy. We investigate epithelial changes in the plasma membrane, cytoskeleton, membrane-cytoskeletal interface, and the extracellular glycoprotein network for receptivity. We are using a number of approaches, including molecular biology, cell culture, transcriptomic, proteomics, gene manipulation by the latest technologies such as CRISPR/CAS9, and in vitro implantation models.

Our recent work has made an important discovery: the human uterine surface is covered by an anti-adhesive barrier for most of the woman’s reproductive cycle. This barrier is likely to protect the uterus from microbial infection; however, it also inhibits embryo implantation. For the uterus to be receptive to an embryo, this barrier must undergo a regulated removal process. Importantly, we now believe that a failure to remove this barrier is likely to be associated with implantation failure and uterine infertility. We are proving this novel concept by investigating a large glycoprotein that has not previously been described in the uterus.

We also study a number of other regulatory molecules, for example proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family. PCs regulate post-translational modifications of various proteins to convert them from non-active precursors into bioactive forms. PCs are considered to be promising targets for therapeutic applications as they are “master switch” proteins involved in various processes.

Our work has established that PC6 is a critical regulator of uterine receptivity. It is up-regulated in the human uterus specifically when it is receptive, and knockdown of PC6 in the mouse uterus inhibits embryo implantation. We have also shown that dys-regulation of PC6 is associated with infertility in women. We are currently focusing on the functional importance of PC6 in the post-translational modification of several intracellular scaffolding proteins, cell surface receptors and extracellular glycoproteins, including those that are associated with the anti-adhesive uterine barrier.

We also study global gene and protein regulation in the human uterus that is essential for the establishment of receptivity. Our studies have found a number of proteins that differ in their uterine expression between fertile women and those who present with unexplained infertility; these proteins are thus potential biomarkers of receptivity. We are currently investigating whether these proteins could be used to develop new tests and therapies to diagnose and treat uterine receptivity and implantation failure.

Collaborators

Prof Luk Rombauts (Monash IVF, Australia)
Prof Beverley Vollenhoven (Monash IVF, Australia)
A/Prof Louise Hull (The University of Adelaide, Adelaide, Australia)
Dr Bruce Lessey (Greenville Memorial Hospital, South Carolina, USA)
Dr Steven Young (University of North Carolina at Chapel Hill, North Carolina, USA)
Dr Maxine Scelwyn (Anat Pathology)
Prof Hilde Van de Velde (Universitair Ziekenhuis Brussle, Brussels, Belgium)