The role of uterine NK cell subsets in mediating placental implantation

胎盘在怀孕初期植入子宫内膜。有时这不会正确发生，妊娠失败，例如早期妊娠失败。然而，有时胎盘确实植入，但不完全。在这种情况下，我们倾向于在怀孕结束时看到问题，如先兆子痫，婴儿生长不正常，早产。所有这些都可能导致早产，每年影响1500万婴儿，其中100万婴儿死亡。在那些存活下来的婴儿中，十分之一将有残疾。因此，对胎盘植入方式的研究不仅有可能帮助女性怀孕，而且还可以通过避免婴儿过早出生来改善婴儿的健康。子宫内膜富含被称为“子宫自然杀伤细胞”或“uNK”的免疫细胞。这些细胞被认为有助于胎盘植入，但我们还不知道如何。我们最近还发现有三种类型的uNK：“uNK 1”，“uNK 2”和“uNK 3”。每种NK细胞都可能有不同的作用，也许只有一种对胎盘着床至关重要。我想找出哪种子宫NK细胞亚群介导胎盘着床，以及它是如何做到的。为了做到这一点，我将观察到来自来医院安装避孕线圈的有生育能力的妇女的子宫内膜样本，与参加我们生育诊所的妇女相比，她们要么经历了两次以上的流产，要么在试管婴儿后两次以上的植入失败。我将使用一种称为“流式细胞术”的技术，一次观察一个参与者的细胞，并找出每个细胞有多少，以及它们有多活跃。如果有胎盘植入问题的妇女中有一个特定的亚群数量较少或活跃，这将表明这些细胞对植入很重要。为了支持我的临床结论，我还将做一些更深入的实验室工作。我将用真实的胎盘细胞开发两种胎盘植入模型，一种在微芯片中，一种在培养皿中。然后，我将看到添加每个uNK亚群的纯制剂如何改变胎盘细胞在这两个模型中的行为方式：当我添加对植入重要的亚群时，它将改善胎盘细胞的生长和迁移。我将使用这些植入模型来帮助我了解uNK如何帮助胎盘植入。例如，我可以阻断uNK产生的某些分子的作用：如果这些分子对着床很重要，阻断它们将使胎盘细胞生长和移动不那么好。相反，如果我添加更多的这些分子，它们对着床很重要，它们将促进胎盘细胞的生长和迁移。进行这些实验将使我能够确定哪一个uNK亚群在以胎盘着床不良为特征的临床条件下不能正常工作，并在两个实验室着床模型中证实我的发现。我也将使用这些模型来开始鉴定uNK制造的分子，以帮助促进植入。这将是开发诊断工具的重要第一步，以确定可能患有因植入不足引起的妊娠障碍的妇女，甚至可能促进可以促进胎盘植入的干预措施，最终减少与植入不足相关的早产负担。

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.