Viruses can cause complications during pregnancy, such as preeclampsia or risks to fetal development. New Yale research finds that these complications may be caused by viruses triggering inflammation that affects the function of the uterine lining.
“The inner lining of the uterus has to prepare itself every month in order to become receptive to a fertilized egg,” says Mancy Tong, PhD, assistant professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine. “It turns into the decidua, a highly specialized and dynamic tissue. We believe that the decidua plays a central role in controlling the success of placental development.”
Tong is senior author of a new study published in Reproduction & Fertility that found viral infections inhibited the process by which the decidua forms, known as decidualization. This, in turn, negatively impacted placental development and fetal growth.
The study, which recently won a best paper award from the Perinatal Research Society, is part of the Tong Lab’s research into the impact of inflammation on fetal and maternal health. Tong and her collaborators hope that their work will eventually guide screening practices to help families prepare for pregnancy.
Inflammation in models of the uterus
Inflammation is a natural defense mechanism against pathogens like viruses and bacteria, but it can also harm body tissues and systems. “It’s an internal balancing act. We need a little bit of inflammation for successful implantation, but not too much,” says Tong.
To better understand how excess inflammation affects placental and fetal development, Tong and her team used synthetic double-stranded RNA (dsRNA) to mimic a viral infection in different models of decidualization.
“What my lab and I are interested in is the impact of inflammation,” Tong says. “We’re not trying to model any one particular virus. Rather, we’ve taken double-stranded RNA as a generalized model to activate inflammation that follows initial infection.”
Tong and her lab used three models to approximate the conditions of a human uterus. Their first model was cultured human endometrial stromal cells, which are what undergo decidualization in the uterus. They exposed these cells to the dsRNA for 48 hours and then stimulated them with hormones to trigger decidualization.
“We first showed that if the cells were inflamed, decidualization was dampened,” Tongs says. When exposed to viral infection, the cultured cells secreted far fewer of the proteins associated with decidualization. “The next question is if decidualization is dampened, then is the endometrium not prepared for implantation and growing the placenta?”
Tong and her collaborators then tested the impact of inflammation on decidualization and placental development in mouse models. They exposed the mice to dsRNA shortly after fertilization.
“Then 15 days later, when we looked at placental and fetal development, we saw that the placentas were malformed, they did not express adequate nutrient transporters, and the fetuses were smaller,” says Tong.
Testing the effect in 3D uterine models
Mouse models and cell cultures are the traditional ways to study uterine and placental biology, but the researchers wanted a model closer to the human reproductive system. They collaborated with researchers in the United Kingdom who had produced synthetic uteruses made of cloned stromal and epithelial cells. These 3D uterine assembloids, as they’re known, are more advanced than previous models because the two cell types together in 3D more closely resemble the uterine lining than do cultures of a single cell type. With these assembloids, the researchers could similarly trigger decidualization in the stromal cells.
“Reproductive biologists around the world are trying to model a tissue that we cannot access in women because pregnancy is such a delicate time,” says Tong. “Assembloids are our way of expanding on what we can do in 2D cells into more physiologically relevant 3D structures.”
In the 3D assembloids, following exposure of the dsRNA, Tong and her team recorded increased markers of inflammation and reduced decidualization.
Across all three models, the endometrium was exposed to dsRNA very early in both decidualization and pregnancy. There is previous research into the impact of inflammation on placental development, but generally, the inflammatory insult is added later in the pregnancy when the placenta is already partially developed.
“The most significant finding from our mouse model is that even when inflammation occurs in the mother very early on, the consequences last to the end of pregnancy,” Tong says. This could suggest that there is a wider window of time in which a viral infection could have a significant impact on pregnancy.
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Tong says that she and her lab are continuing their research into the effects of inflammation on early pregnancy, specifically how the decidua communicates with the placenta. She says right now, maternal-placenta communication remains a “black box” but is likely related to successful fetal development.
“We saw some evidence of this in our mouse models. Now we want to look at the mechanism of how the mother, via the endometrium, is communicating with the placenta,” says Tong. “We want to know if this is mainly mediated through extracellular vesicles, soluble factors, direct cell-to-cell contact, or through another cell type present at the interface, like immune cells, for example.”
Towards better pregnancy screening
In the future, Tong hopes this research could lead to better screening practices for people trying to plan a pregnancy, especially those trying to find an ideal time for in vitro fertilization (IVF).
“If we could use these models to identify novel factors that contribute to successful placental development, we could develop new ways to measure these factors in patients,” says Tong. “Then, we could better predict the timing for embryo transfer or develop new therapies to hopefully lead to successful implantation and a healthy pregnancy.”
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