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Placenta Map Reveals Source of Infection-Related Pregnancy Complications

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During early-stage development, the fetus relies heavily on the placental barrier for protection. The mechanisms infections use to cross the placenta are poorly understood due to limitations in the laboratory models traditionally used to study infection pathways in the human placenta.

Researchers have now created the first panoramic view of infection pathways in the human placenta using ex vivo explant models, or “mini placentas” from human samples. This placenta map could highlight potential drug targets to develop pregnancy-safe therapies for diseases that can cause severe pregnancy complications.

The results were published in the journal Cell Systems and form part of the wider Human Cell Atlas consortium, which aims to map every cell type in the human body to transform our understanding of health and disease.

A fetus’ first line of defense

The study focused on the pathways involved in malaria, toxoplasmosis and listeria infection. The three pathogens responsible for these diseases, Plasmodium falciparum (P. falciparum), Toxoplasma gondii (T. gondii) and Listeria monocytogenes (L. monocytogenes), can cause pregnancy complications such as miscarriage, low birth weight, stillbirth and developmental anomalies.

Infections with P. falciparum are of particular concern due to its high prevalence worldwide, particularly in Sub-Saharan Africa and parts of Southeast Asia where the malaria parasite is endemic.

The placenta is the first organ to be generated by the embryo, its principal function is to provide the fetus with water and nutrients while blocking pathogens and toxins. During early-stage development, the fetus is particularly vulnerable to pathogens as the immune response is not fully established. They therefore rely heavily on the placental barrier for protection.

T. gondii and L. monocytogenes can cross the placenta while P. falciparum can attach to the outside, making these pathogens ideal targets for studying infection pathways in the placenta.

“While the consequences of these infections during pregnancy are widely known, the mechanisms and pathways involved are much less understood, and we wanted to address this gap in knowledge in our research,” Dr. Roser Vento-Tormo, co-senior author from the Wellcome Sanger Institute told Technology Networks.

“We hope that our research can be used by the scientific community worldwide to help develop new ways to understand and treat pregnancy complications that impact millions of lives every year.”

“Mini placentas” help map infection pathways

Previous studies on the placenta have often relied on mouse models which exhibit substantial differences from the human placenta. To represent the impact of infection more accurately on human placentas the scientists created ex vivo placenta explant models.

“The ‘mini placentas’, also known as placental explants, are derived from human donations and can model all placental cell types for up to three days,” said Elias Ruiz-Morales, co-first author from the Wellcome Sanger Institute.

“This includes cell types that are not normally supported in traditional placental models, such as immune, vasculature and stromal cells. Having access to models with these cell types is fundamental to being able to study the effects of infections in the tissue and the placental innate immune responses.”

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These models have been used previously to study the placenta in other contexts such as changes in hormone levels and metabolism, maternal cytokines, and drug responses to chemicals in utero.

Ruiz-Morales explains these models could be developed further to study placental responses for longer and incorporate the maternal microenvironment: “Continually improving ‘mini-placenta’ models will help build an accurate, in-depth, picture of what happens during pregnancy and aid researchers worldwide.”

Placental immune cells are activated by infection

Using models of the human placenta, the researchers found that Hofbauer cells were activated in all three types of infection – but in different pathways.

Hofbauer cells are a specific subset of macrophages and are the only immune cells found in the core of the placenta. They are usually considered tolerogenic and support physiological functions of the tissue such as blood vessel formation. This is the first time they have been shown to play a defensive role against pathogens in the human placenta.

“Studying these cells in vivo and their role in fighting infections within the placenta has been a major challenge and, before now, a clear defensive role had not been described,” said Dr. Vento-Tormo. “We demonstrate that in addition to the support roles that these cells have, they also have a pivotal role in protecting the placenta against infection.”

“Our work discovered, at high resolution, distinct pathogen-specific pathways activated in Hofbauer cells in response to different infections, highlighting that these immune cells have the capability to adapt to various threats.”

The discovery that Hofbauer cells have specific responses to different pathogens could potentially inform the design and precision of treatments. Utilizing environmental cues to modulate the activity and function of macrophages in the body could enable the development of therapies that utilize the body’s immune system to fight the pathogen.

“For example, we uncovered how T. gondii uses Hofbauer cells to replicate and spread around the body. Modifying the described pathways dysregulated in Hofbauer cells during T. gondii infection could help slow and possibly stop disease progression,” commented Dr. Vento-Tormo.

Targeting inflammation pathways for treatments

All three infections induced a general inflammatory response in the placenta which dysregulated placental functions. This suggests that secondary inflammation may be the cause of some pregnancy complications.

“Inflammatory responses come with certain trade-offs, including disrupting normal blood vessel formation in the placenta,” said Dr. Vento-Tormo. “This process is fundamental for the placenta’s primary function as a nutrient provider and interference with this could affect fetal development.”

During inflammation, immune cell receptors are expressed on trophoblasts (specialized epithelial cells in the placenta), leading to blood cell recruitment and activation. Activated blood cells can damage the tissue because of an unspecific immune response.

“All of these factors might contribute to complications during pregnancy, and could increase the risk of miscarriage and stillbirth,” said Dr. Vento-Tormo.

Targeting these inflammation pathways could lead to pregnancy-specific treatment for infections, which is not currently possible.

Dr. Roser Vento-Tormo and Elias Ruiz-Morales were speaking to Blake Forman, Senior Science Writer for Technology Networks.

About the interviewees:

Dr. Roser Vento-Tormo is a group leader at the Wellcome Sanger Institute. She earned her PhD in health and life sciences from the University of Barcelona. Her research is focused on the adaptation of immune cells in tissues and their function in steady state and inflammation.

Elias Ruiz-Morales is a PhD student at the Wellcome Sanger Institute and the University of Cambridge. He earned his BSc in genomic sciences from the National Autonomous University of Mexico. His research involves using single-cell and single-nuclei transcriptomics to study the host-pathogen interactions at the placental-maternal interface in humans.

Reference: Hoo R, Ruiz-Morales ER, Kelava I, et al. Acute response to pathogens in the early human placenta at single-cell resolution. Cell Syst. 2024;15(5):425-444.e9. doi: 10.1016/j.cels.2024.04.002