Novel imaging platform allows researchers to study placental development in pregnant mice

DURHAM, N.C. — Physicians and biomedical engineers at Duke University have developed a method to visualize the growth of a placenta throughout a mouse’s pregnancy. By coupling an implantable window with ultrafast imaging tools, the approach provides the first opportunity to track placental development to better understand how the organ functions during pregnancy.

This new perspective gives researchers a precise way to examine how lifestyle factors like alcohol consumption and health complications like inflammation can affect the placenta and potentially lead to adverse pregnancy outcomes.

The research appears March 20 as the cover article in Science Advances.

The placenta is a highly vascular organ that forms between the mother and fetus, providing oxygen and nutrients while removing waste. Even though problems in its development can lead to a cadre of health issues for both parties, little is known about how it grows and functions and there are few effective treatments for when things go wrong.

Much of this is because the organ has proved difficult to study. Researchers rely on mouse models, because mouse and human placentas share similar anatomical, cellular and molecular features. But even this is tricky, as the organ is deep in the abdominal cavity and is constantly moving, making it a challenge to image with traditional tools.

A new approach developed by Junjie Yao, associate professor of biomedical engineering at Duke, and Dr. Liping Feng, associate professor of obstetrics and gynecology at the Duke University School of Medicine, bypasses these problems by creating a safe, implantable window that provides direct access to the placenta in pregnant mice. By pairing this tool with the imaging technique ultrafast functional photoacoustic microscopy (UFF-PAM), the team can capture highly detailed images of the blood flow and oxygen metabolism of the complex organ.

“UFF-PAM can achieve high imaging speed, so the images aren’t disrupted by breathing or the motions of the embryo or placenta,” said Yao. “By using it with the implantable window, we can see how the placenta grows, how it recruits new blood vessels, how it feeds the fetus, and other drastic changes in both healthy and diseased states over the 20-day gestational period.”

Traditional photoacoustic microscopy (PAM) uses the properties of light and sound to capture detailed images of organs, tissues and cells throughout the body. The technique uses a laser to send light into a targeted tissue or cell. When the laser hits the cell, it heats up and expands instantaneously, creating an ultrasonic wave that travels back to a sensor. The UFF-PAM system relies on a combination of hardware advancements and machine learning algorithms to upgrade this technique, making it faster and more sensitive.

The team first used their technique to study placental blood supplies during a healthy pregnancy. From day seven to day 19 of fetal development, the team tracked blood vessel size, vessel density and oxygen levels.

Oxygen levels dropped slightly from day seven to day 10, while both blood vessel diameter and density increased by more than 200%.

“We normally see that low-oxygen environment in tumors, not in organs,” said Yao. “But the highly vascular placenta grows quickly, just like the tumors. The low-oxygen environment triggers the placenta to grow a lot of vessels to facilitate the exchange of nutrients, oxygen and waste products between the mother and the fast-developing fetus. As the vessels develop, the oxygen level rises.”

Next, the team explored how different lifestyle factors and health complications affected the development of the placenta and health of the fetus. Starting with alcohol consumption, they injected ethanol into the abdominal cavity and used UFF-PAM to observe the changes in the organ’s blood dynamics. While the alcohol caused a small decrease in the total blood vessel density, there was a significant initial increase in oxygen levels in the placenta.

“Alcohol consumption during pregnancy can affect the developing placenta and fetus, but nobody really knows why or how,” said Feng. “Our study provides evidence that alcohol can affect placental development by altering its blood flow and oxygen metabolism.”

The team also tested a model that mimicked inflammation caused by an immune response or infection. During pregnancy, the placenta helps prevent the mother’s immune system from attacking and rejecting the fetus. However, this immune barrier can be disrupted, leading to pregnancy complications such as pregnancy loss, preterm birth, smaller babies, and preeclampsia. However, it is not clear how inflammation or infection affects the placental blood flow. In their model, the team observed that an inflammatory reaction resulted in significantly fewer and smaller blood vessels in the mouse’s placenta. These placental vasculature changes were accompanied by higher oxygen levels compared to the healthy control group, so the placenta wasn’t triggered to make more blood vessels by being hypoxic.

“Using this novel imaging tool in these mouse models, we can provide detailed insights into the placental structure, vascularization, and function in real-time,” Feng said.

Now that the team has a proof of concept, they plan to study more specific conditions and how they affect the placenta.

“These tools not only help us to understand how pregnancy complications happen but also provide a pre-clinical tool for drug screening,” Feng said. They also want to test how common drugs, like aspirin, affect pregnancy.

“There is so much we don’t know about pregnancy, especially from a fundamental research perspective,” Yao said. “We’re hopeful that this tool can help us tackle those long-standing problems and mysteries so we can make pregnancy safer.”