Placental Research
The placenta is essential for the maintenance of pregnancy. The prominent function of the placenta is in the transfer of nutrients, gases, and waste products between the mother and fetus; it is effectively the lung, gut, and kidney of the fetus. The placenta is also involved in the production of hormones that are involved in the maintenance of pregnancy and the initiation of labor. Another important function of the placenta is to act as a selective immunological barrier, so that the mother's immune system does not attack the fetal allograft. Thus, perturbations in one of its many functions can have dire consequences for the fetus, ranging from IUGR to fetal death. This section highlights some findings from PPB-supported grants in placental research over the last five years and illustrates the multifaceted nature of this research.
Trophoblast cells are essential components of the placenta. Early in pregnancy, one type of trophoblast, cytotrophoblast cells, are involved in uterine invasion, grafting the embryo onto the mother and establishing a blood supply. During placental development, these cells differentiate into syncytiotrophoblast cells, which form the continuous surface of the placental villous that bathes in the maternal blood. The syncytiotrophoblast cells are primarily involved in nutrient, gas, and waste product exchange transport between the maternal and fetal circulation. Because of the essential roles both these cell types play in the maintenance of pregnancy, it is essential to understand the mechanisms involved in trophoblast lineage determination. One PPB-supported investigator, taking advantage of powerful RNA-expression microarray technology, characterized the process of cell differentiation using a cell culture model system (Recent Prog Horm Res 2003; 58:263-81). After analyzing approximately 7,000 genes for RNA expression levels, the researcher found a total of 397 genes that changed during the differentiation process; 141 genes were upregulated, while 256 were down-regulated. These genes were grouped into functional categories that were either strongly induced or repressed during the differentiation process and were found to be tightly coupled to key morphological changes. Thus, trophoblast differentiation comprises a highly dynamic process that affects the expression of classes of genes based on their functionality.
As mentioned earlier, preeclampsia is a leading cause of maternal morbidity and mortality. It is widely speculated that factors emanating from the placenta are responsible for the disease by damaging the vascular endothelium. One group of investigators has been studying the possible role of oxidative stress in the etiology of preeclampsia (Am J Pathol 2000; 156:321-31). These researchers believed that post-ischemic reperfusion of the placenta results in excess levels of reactive oxygen species and their metabolites, which, in turn, cause these factors to enter the maternal circulation and result in systemic vascular endothelial damage. To learn more, the researchers explored whether xanthine oxidase, a key enzyme involved in the production of reactive oxygen species, mediates oxidative stress in placentas from women with preeclampsia. They found that a subpopulation of cytotrophoblasts in preeclamptic women had increased xanthine oxidase levels. In addition, the expression level of superoxide dismutase, another enzyme involved in degrading reactive oxygen species that is generated by xanthine oxidase, was reduced in the same cells. Furthermore, immunostaining for nitrotyrosine, an indicator of oxidative damage, showed a high level of damage in these cells and in the villous vessels. These results indicate that placental cells have an increased capacity to generate reactive oxygen species in preeclampsia, supporting a role for oxidative stress in the disorder.
Placenta growth factors (PlGFs), a family of proteins produced in the placenta by trophoblast cells, are primarily involved in regulating placental angiogenesis in the placenta, and trophoblast function and survival. PlGFs can act either in a paracrine fashion to influence vascularity, or in an autocrine fashion to influence trophoblast function. Recent studies have demonstrated that PlGFs may have divergent functions. For example, angiogenesis may be promoted or inhibited depending on the particular PlGF isoform under study. Until recently, there had been only three known PlGF isoforms (PlGFl-3). A PPB-funded investigator discovered a fourth isoform, called PlGF4 (J Reprod Immunol 2003; 60:53-60). Like PlGF2, PlGF4 contains a heparin-binding domain, which suggests that it remains bound to the plasma membrane and probably acts in an autocrine manner. Further functional studies of the PlGF4 protein isoform and its expression during gestation will help to clarify its role in mediating placental vascularity and trophoblast function.
As a result of trophoblast differentiation, the syncytiotrophoblast produces pregnancy-specific peptides, such as chorionic somatomammotropin (CS), also known as placental lactogen. CS is a member of the growth hormone family and has significant effects on both mother and fetus. It plays a role in regulating fetal growth, mammary development, and lactogenesis, and in maternal intermediary metabolism. The regulation of placental CS production, however, is not well understood. Using the baboon as a nonhuman primate model, a team of PPB-supported investigators previously showed that estrogen accelerated the morphological differentiation of cytotrophoblast during the first half of pregnancy, and stimulated the functional maturation of the syncytiotrophoblast in the second half of pregnancy with regard to steroidogenesis. This team is now investigating whether estrogen also regulates CS production by the syncytiotrophoblast (J Clin Endocr Metab 2003; 88:4316-4323). This research found that estrogen suppressed CS production during the first trimester, but had no effect on key steroidogenic enzymes. Together, these results indicate that estrogen has very different and specific actions on steroid and peptide hormone biosynthesis within the placental trophoblast. This differential effect may be important in regulating placental function and promoting fetal-placental during the course of pregnancy.
Natural killer (NK) cells are the predominant immune cells present in rodent and human placental implantation sites. Phenotypically, uterine NK cells undergo a gestational-dependent transformation during the course of pregnancy. NK cells expand in number and differentiate, but do not acquire a classic activation of cell killing. In the rodent, trophoblast cells produce a large number of protein hormones that belong to the prolactin family, one of which, called PLP-A, has been shown to specifically interact with rodent uterine-NK cells within the uteroplacental compartment, inhibiting NK-cell killing activity. A PPB-funded investigator studied the role of PLP-A as a potential modulator of NK cells at the maternal-fetal interface (Mol Cell Endocrinol 2003; 204:65-74). He found that PLP-A interactions with NK cells are not mediated by receptors known to be utilized by modulators of NK activity, such as IL-2, IL-7, IL-12, or IL-15. In contrast, PLP-A suppresses the ability of NK cells to produce interferon-gamma, a key mediator of NK-cell function. This latter finding may be especially important because it has been reported that interferon-gamma also inhibits trophoblast cell outgrowth. Consequently, the inhibition of interferon-gamma production by PLP-A in NK cells may be important in permitting continued placental development.
The Branch also supports efforts in other areas of placental research as they relate to both normal and disease processes, including:
- The role of vasodilators, vasoconstrictors, and factors that are produced by the placenta in relation to preeclampsia and IUGR
- Hormonal interactions between the fetus and placenta
- The autocrine, paracrine, and endocrine roles of PlGFs and cytokines, including studies to determine the effects of these proteins on placental growth, differentiation, and function
- Signal transduction mechanisms at the cellular level
Additional studies are currently supported by the Branch in the following areas: angiogenesis, infectious agents, gene regulation, metabolism, growth and differentiation, morphology, growth factors and cytokines, nutrients, hormone production and regulation, transport, immunology, and vascular function. Undoubtedly, new areas of research will arise in the future and the emphasis in particular areas will shift, depending on future discoveries and developing technologies.
first | previous | next | last
