Modeling human trophoblast-NK cell interactions in term and preterm birth

项目总结/文摘

Project Summary/Abstract The human placenta is a semi-allogeneic tissue whose growth and development requires tolerance by the maternal immune system. In fact, the maternal immune system faces a challenge during pregnancy: to maintain tolerance toward foreign fetal alloantigens while simultaneously staging a response to potential pathogens at the maternal-fetal interface. The mechanisms through which placental cells evade maternal immune recognition are poorly understood, particularly in the context of human pregnancy. The uterine lining, called decidua, is a particularly-understudied and important microenvironment, because it is the interface where placental cells called extravillous trophoblast (EVT) come in close contact with maternal immune cells, of which decidual natural killer (dNK) cells are the most abundant. EVT are highly invasive cells which are required for proper remodeling of the maternal uterine lining, including vascular remodeling which leads to establishment of maternal blood flow to the placenta. Interactions between placental EVT and decidual leukocytes are known to facilitate maternal vascular remodeling by EVT and limit the extent of EVT invasion into the uterine wall. Indeed, problems in preterm birth could result from inappropriate responses by dNK cells. Unfortunately, interactions between dNK and trophoblasts are difficult to study in an ongoing pregnancy, due to lack of access to the decidual compartment, where these important interactions occur. While animal models have offered some insights into these processes, they do not accurately model human placentation and pregnancy. The goal of the original R01 proposal is to evaluate the decidual cell population in both term and preterm birth, then to combine this knowledge with the latest technologies in regenerative medicine to develop in vitro models for the study of dNK-EVT interactions. Specifically, we proposed to generate matched maternal and placental induced pluripotent stem cells (iPSC), and differentiate these cells into dNK cells and EVT, respectively, in order to model interactions between these two cell types. Given the known association between male fetal sex and risk of preterm birth, we had focused our efforts on characterizing, banking, and reprogramming cells from mom:male baby pairs in the original application. However, to fully understand mechanisms that predispose to sPTB, it would be best to compare these data to those from mom:female baby pairs. Therefore, we now propose to characterize, bank, and reprogram cells from mom:female placenta pairs for this administrative supplement. Successful completion of this proposal will establish a reproducible and manipulatable model system for studying interactions between the maternal immune system and both the male and female placenta.