While vital for a healthy pregnancy, the placenta is not well understood. Researchers now take advantage of spatial biology approaches to plumb its secrets.
Stephanie joined Drug Discovery News as an Assistant Editor in 2021. She earned her PhD from the University of California Los Angeles in 2019 and has written for Discover Magazine,...
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For an organ essential to life, scientists know surprisingly little about the placenta. It may be a transient organ that only appears during pregnancy, but the placenta provides a vital link between the developing fetus and mom.
“Pregnancy is not a disease, but it's a physiologic state,” said Yalda Afshar, a maternal-fetal medicine physician-scientist at the University of California, Los Angeles. “Unfortunately, in women's health, we're a little bit behind in understanding some of the basic biology behind one of the most common events.”
During a healthy pregnancy, cells from the embryo called trophoblasts implant in the mucosal layer of the uterine wall, which turns into a structure called the decidua (1). Further specialized trophoblasts then invade the decidua, and the fetal cells begin to differentiate and grow to form the placenta.
If trophoblasts don’t infiltrate the decidua properly, life-threatening conditions can arise for both the fetus and the mother. These include preeclampsia, placenta previa, and placenta accreta spectrum disorder, among others. When conditions like these come about, there is very little that clinicians can do.
“The treatment options are really limited. Partially, it's because we don't really understand what's going on,” said Junjie Yao, a biomedical engineer at Duke University.
To change that, researchers leverage advances in spatial biology techniques to investigate the placenta in more detail than ever before. Through innovative in situ imaging approaches, new computational tools, and single cell and spatial transcriptomics, scientists are determined to let the placenta remain a mystery no longer.
From frogs to placental windows
Before Yao began studying the placenta, he was enthralled with glass frogs. “These [are] very magical frogs from South America. They can become much more transparent when they're sleeping, so they can hide from their predators,” Yao said.
How exactly these frogs became transparent was unknown, so Yao and his colleagues developed new imaging systems to figure it out. They discovered that the frogs removed the blood from their circulatory systems and packed it into their livers while they slept (2).
As the head of a “very hardcore imaging lab,” Yao explained that he and his research team develop new imaging technologies to answer unresolved biological questions; the mysterious glass frogs were just one example. One of his team’s latest questions focused on how to get high-resolution images of the placenta over the course of development. One way to do this is to study placental development in an animal model using a window that researchers implant into the animal’s abdomen.
“People have been developing windows for high resolution imaging, for example, for the brain, for other organs, liver, even the embryo itself,” Yao said, but not for the placenta. “When I talk to pediatric surgeons, the answer is always that the placenta is very delicate.”
Imaging windows exert pressure on the walls of the biological tissue they are sandwiched into and consequently on the placenta itself, which could affect its development. Windows can also allow too much heat to escape, leaving the placenta too cold. Finally, if not built with placental growth in mind, an imaging window could leave the placenta with too little space to develop completely.
Yao and his team, however, were up for the challenge.
They carefully designed their placental window to sit over one of a pregnant mouse’s embryos, and they watched the placenta develop over the course of 12 days, from embryonic day seven to embryonic day 19 (3). All of the mice that were born after being observed in the placental window developed into healthy adult mice, indicating that the window did not adversely affect their long-term development.
With a successful imaging window in place, Yao and his team just needed the perfect imaging tool to study the placenta. They started with photoacoustic microscopy (PAM), which uses both light and sound to image deep inside tissues. In this technique, the researchers shoot a laser pulse at the tissue they want to image, and some photons from the laser get absorbed by the molecules in the tissue. Just like in a car parked outside in the summertime, the photons heat up the tissue. This increase in heat causes the molecules to expand and push against the neighboring molecules in the tissue. The pressure from one molecule on the other propagates as a pressure wave through the tissue, and the researchers detect it as a sound wave via an ultrasound.
“By doing the ultrasound detection, we can achieve a deeper imaging depth and better resolution, and you still keep the functional information of the light,” Yao explained. “This whole process is really a physical combination of light and sound, but with their best merits. So, it's a great technology especially suitable for studying functions and molecular information of tissues.”
I was really amazed by the delicacy of this organ. The information is so rich, especially when you're looking at the early stages of placenta. I'm just so totally taken away by how complex the biology is, even for a transient organ.
– Junjie Yao, Duke University
Their next challenge was to find a way to use PAM on a sample that is not still. Because it is located deep within the body, the placenta is always moving. It’s subject to motion from the embryo and the mother’s breath, so Yao and his team developed a technique called ultrafast functional PAM imaging that could capture an image faster than the placenta moves. With their imaging technology and placental window ready to go, the team could finally see exactly how the mouse placenta changed over the course of a pregnancy.
“I was really amazed by the delicacy of this organ,” said Yao. “The information is so rich, especially when you're looking at the early stages of placenta. I'm just so totally taken away by how complex the biology is, even for a transient organ.”
Just as the human placenta develops in a hypoxic environment, Yao and his team observed that the mouse placenta does as well (4). This hypoxia signals to the placenta to form blood vessels out of the maternal arteries in the uterus, allowing the fetus access to nutrients and oxygen.
They then assessed how different factors affected the placenta, starting with alcohol exposure. While alcohol consumption during pregnancy is harmful to the fetus, alcohol’s influence on placental development was not as well understood. The researchers injected a small amount of alcohol into the pregnant mouse’s abdominal cavity, and over the course of ten minutes, they saw a dramatic increase in the oxygenation level in the placenta.
“That actually gives the placenta a wrong signal. They say, ‘Ah, I have too much oxygen. No, I don't have to develop more blood vessels,’ with this just a single sip. Imagine if it's a chronic drink,” Yao said. “We always knew it was not good drinking alcohol during pregnancy. This is the first time we actually saw it clearly down to the single vessel level.”
Yao and his team also investigated how a model of maternal cardiac arrest and chronic inflammation affected the placenta as well as monitored how an adeno-associated virus, which is often used for gene therapy delivery, moved through the placenta. Moving forward, Yao wants to use this placental imaging system to study how other environmental stressors such as climate change and water pollutants such as per- and polyfluoroalkyl substances (PFAS) influence the placenta and overall pregnancy.
Yao and his team plan to make their imaging system even better. “You cannot put everybody under the window, so we're developing technologies right now to do this [in a] totally non-invasive [way],” he said.
A placental Google Maps
When Roser Vento-Tormo, now a genomics and bioinformatics scientist at the Wellcome Sanger Institute, was a postdoctoral researcher, she became fascinated with the unique immune interface at the decidua and the placenta where maternal and fetal cells happily mingle without conflict.
“It was very interesting to know how the immune cells really make this happen. Instead of rejecting the tissue, they collaborate with the tissue to ensure the proper implantation and embryo development,” she said. “That was the very first thing that got me into going into the placenta.”
As a postdoctoral researcher Vento-Tormo used single cell transcriptomics to profile the transcriptomes of approximately 70,000 single cells from the placenta, which included fetal cells from the placenta, maternal immune cells in the decidua, and many other cell types (5). While her findings revealed the gene expression programs of cells present in the placenta and decidua, it lacked an important component: spatial information.
“Their identity depends on the spatial location,” Vento-Tormo explained. As trophoblasts, the specialized placental cells, migrate in the decidua, they acquire new identities. “Having the spatial [data] allow us to understand the process and what are the cells doing,” she said. She also wanted to know how the migrating trophoblasts interacted and communicated with maternal decidual cells as the placenta developed.
To answer those questions, Vento-Tormo and her colleagues performed both single cell transcriptomics and spatial transcriptomics on placental samples from early pregnancy that were collected by Ashley Moffett, a reproductive immunologist at Cambridge University (6). They acquired a wealth of spatial information, including how fetal placental and maternal decidual cells interacted with each other. In collaboration with Oliver Stegle’s group at the European Molecular Biology Laboratory, Vento-Tormo and her team even developed a new statistical tool to model cell migration to create a complete map of placental cell migration and invasion into the uterus during the first trimester of pregnancy.
They identified potential interactions between the placental cells and maternal immune cells, supporting prior research that showed that maternal immune cells support a healthy pregnancy, not hinder it. She and her team used this new single cell and spatial information to validate their in vitro placental models. Their new findings will inform in vitro placental models with even more complexity such as incorporating cells from two different individuals — mother and fetus — in the same model.
Now that she and her team have a map of healthy early placental development, Vento-Tormo wants to find out how those instructions go awry in diseases such as preeclampsia or placenta accreta. She is excited about the potential that single cell and spatial biology methods have to answer these kinds of questions.
“This is quite a black box, so we know very little. The good thing about using -omics is that it is unbiased,” she said. “The thing that is most exciting [is] that we started uncovering the secret of this environment without really knowing much about what's happening.”
The seed and the soil in placenta accreta
During a normal birth, the mother delivers the child followed by the placenta, but sometimes the placenta invades the decidua so tightly that it doesn’t detach when it should. This condition is called placenta accreta. It occurs in one in 272 births, and it can be deadly (7).
“Early detection of accreta is imperative to improve the outcome of that pregnant person because they need to be at a center with blood and expert surgeons,” said Afshar. “If it's diagnosed in a center without those, women die from this because of hemorrhage.”
The biggest risk factor for placenta accreta is history of a prior Cesarean (C-) section, but placenta previa (when the placenta attaches low in the uterus, sometimes covering the cervix) and in vitro fertilization are risk factors as well.
“My interest in placenta accreta is, at the end of the day, really inspired by the women I take care of in the clinic. They come to me scared and appropriately apprehensive of why them? And I don't know why them,” Afshar said.
To unpack the molecular mechanisms that underly placenta accreta, Afshar and her colleagues took a single cell and spatial biology approach (8). They collected placentas at the time of birth from six patients with placenta accreta and six healthy individuals as controls. This protocol was no small feat, she added, “This is RNA work that you have to do really fresh and quickly, and it doesn't matter what time the baby's born.”
Historically, we always assumed it was the placenta that was this invasive organ that was the culprit, but now there is, I think, enough robust clinical and biological data that it's really not just the placenta.
- Yalda Afshar, University of California, Los Angeles
For the placentas with placenta accreta, the researchers cut a two-centimeter cubed sample of the organ from the part that had adhered to the uterine wall and one from the non-adherent site. For the controls, they took the same sized sample from where the placenta had adhered normally to the uterine wall.
“The placenta is a giant organ, and a lot of work is done on just a tiny little histologic block. But there's so much difference in adherence in placenta accreta. There's one area that's adhered, so what's different about that adherent area versus a non-adherent part?” Afshar asked. “The power of spatial is really to be able to decouple that.”
They found the most differences in gene expression between the cellular populations in the placenta accreta patients and the healthy controls at the sites of adherence, but there were also substantial differences between the adherent and non-adherent sites in the placenta accreta samples as well. They identified transcriptional differences in extracellular matrix genes, growth factors, and angiogenesis. In particular, none of the genes that they identified as upregulated in placenta accreta samples had ever been identified as contributing to the disease before, highlighting the value of the single cell approach.
“Historically, we always assumed it was the placenta that was this invasive organ that was the culprit, but now there is, I think, enough robust clinical and biological data that it's really not just the placenta,” Afshar explained. The maternal decidua plays a significant role too. “It is some kind of lack of a stop signal and a loss of these boundary limits in the implanting pregnancy in that maternal environment that led to this high-risk pregnancy complication.”
Afshar likened this phenomenon to a garden. If the placenta is a seed, “of course it's the decidua that is the soil, and the soil is perturbed.”
She now plans to study the impaired pathways involved in placenta accreta using in vitro models, and she hopes to find surgical ways to prevent placenta accreta from developing in patients who give birth via C-section.
“All of this has implications way broader than accreta. It's scarring. It's fibrosis. How do we translate that to other fibrotic diseases? How do we translate that to better pregnancy outcomes in other normal and non-pathological states?” she asked. “I hope that this work really pushes to understanding why some people develop this, others don't, and approaches to blocking the abnormal placental growth in these regions of scarring.”
References
- Herrick, E.J. and Bordoni, B. Embryology, Placenta. StatPearls (StatPearls Publishing), 2024.
- Taboada, C. et al. Glassfrogs conceal blood in their liver to maintain transparency. Science 378, 1315-1320 (2022).
- Zhu, X. et al. Longitudinal intravital imaging of mouse placenta. Sci Adv 10, eadk1278 (2024).
- Patel, J. et al. Regulation of Hypoxia Inducible Factors (HIF) in Hypoxia and Normoxia During Placental Development. Placenta 31, 951-957 (2010).
- Vento-Tormo, R. et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature 563, 347–353 (2018).
- Arutyunyan, A. et al. Spatial multiomics map of trophoblast development in early pregnancy. Nature 616, 143–151 (2023).
- Mogos, M.F. et al. Recent trends in placenta accreta in the United States and its impact on maternal–fetal morbidity and healthcare-associated costs, 1998–2011. J Matern Fetal Neonatal Med 29, 1077–1082 (2016).
- Afshar, Y. et al. Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium. Am J Obstet Gynecol 230, 443.e1-443.e18 (2024).
