The role of uterine NK cell subsets in mediating placental implantation

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The placenta implants into the lining of the womb at the beginning of pregnancy. Sometimes this does not happen properly and the pregnancy fails, for example by an early pregnancy loss. However, sometimes the placenta does implant, but incompletely. In this case, we tend to see problems at the end of pregnancy, such as pre-eclampsia, the baby not growing properly, and preterm labour. All of these can result in preterm birth, which affects 15 million babies every year, with 1 million of them dying. Of those babies that survive, one in ten will have a disability. Therefore, research into how the placenta implants has the potential not just to help women conceive, but also to improve the health of babies by avoiding them being born too soon.The lining of the womb is rich in immune cells called "uterine natural killer cells", or "uNK". These cells are thought to help the placenta to implant, but we don't yet know how. We have also recently discovered that there are three types of uNK: "uNK1", "uNK2" and "uNK3". Each of these is likely to have different roles, and perhaps only one of them is crucial for placental implantation.I want to find out which uterine NK cell subset mediates placental implantation, and how it does it.To do this, I will look at samples of the lining of the uterus from fertile women who are coming to the hospital to have a contraceptive coil fitted, compared to women attending our fertility clinic either because they have suffered more than two miscarriages, or more than two failures of implantation following IVF. I will use a technique called "flow cytometry" to look at cells from my participants one at a time and find out how many of each cell there are, and how active they are. If one particular subset is less numerous or active in women who have problems with placental implantation, that will suggest that these cells are important for implantation.To back up my conclusions from the clinic, I will also do some more intensive laboratory work. I will develop two models of placental implantation using real placental cells, one in a microchip and one in a dish. I will then see how adding pure preparations of each of the uNK subsets changes the way placental cells behave in these two models: when I add the subset that is important for implantation, it will improve the growth and migration of the placental cells. I will use these models of implantation to help me understand how the uNK help placental implantation. For example, I can block the action of certain molecules that uNK make: if these molecules are important for implantation, blocking them will make the placental cells grow and move less well. Conversely, if I add more of those molecules, and they are important for implantation, they will improve the growth and migration of the placental cells.Doing these experiments will allow me to identify which uNK subset is not working properly in clinical conditions characterised by poor placental implantation, and confirm my finding in two laboratory models of implantation. I will also use these models to begin to identify the molecules uNK make to help promote implantation. This will be an essential first step in developing diagnostic tools to identify women who are likely to suffer from disorders of pregnancy caused by insufficient implantation, and perhaps even promoting interventions that can promote placental implantation, ultimately reducing the burden of preterm birth associated with insufficient implantation.