Guardians of the Womb: The Trophoblast Organoids Reinventing Fetal Safety

Researchers have created a stem cell-based organoid model of the placental barrier, offering a new tool for studying placental function and drug toxicity, potentially improving fetal safety in drug development.

Researchers from Tokyo Medical and Dental University (TMDU) overcome scientific roadblocks and develop a model to assess the biology of the human placental barrier.

During pregnancy, the human placenta plays multiple essential roles, including hormone production and nutrient/waste processing. It also serves as a barrier to protect the developing fetus from external toxic substances. However, the placental barrier can still be breached by certain drugs. In a recent article published in Nature Communications, a team led by researchers at Tokyo Medical and Dental University (TMDU) developed a trophoblast stem (TS) cell-based organoid model of the placental barrier to support further biological research.

Advancements in Placental Modeling

Villi in the human placenta help form the barrier and are surrounded by a layer of cells called trophoblasts. Because the structural nature of villi is critical for its function, cell lines and other methods used to replicate placental physiology in laboratory experiments have proven inadequate. Primary placental cells are also difficult to maintain in culture. Therefore, the TMDU group aimed to develop an effective in vitro model of placental villi using TS cells.

In the human placenta, there are placental villi, and the surface of the villi consists of syncytiotrophoblast, also called barrier cells, that serve as the main barrier against foreign substances. However, some medicines taken by pregnant women can penetrate this placental barrier and have undesirable effects on the fetus. Credit: Department of Diagnostic and Therapeutic Systems Engineering, TMDU

“TS cells have the capacity to differentiate into all kinds of placental cells consisting of the human placenta.,” says Dr. Takeshi Hori, lead author of the study. “However, it has been challenging to make the barrier model using TS cells.”

Developing and Testing the Organoid Model

First of all, the team then generated trophoblast organoids, a type of three-dimensional cell model that can more effectively mimic the structural and biological details of an organ. After testing three types of culture medium, they determined the optimal conditions to support the formation of spherical organoids.

“The outer layer of the organoid contained a single layer of cells called syncytiotrophoblasts,” explains Dr. Hirokazu Kaji, senior author. “This layer effectively displayed the barrier function that we were aiming to mimic with this model.”

Placental organoids generated from human placental stem cells (left), a front view of the placental barrier model (center), and a side view of the barrier model (right image, red-colored cells at the top of the layers indicate barrier cells). Credit: Department of Diagnostic and Therapeutic Systems Engineering, TMDU

Based on the culture conditions of the spherical organoids, the researchers established flatter organoids with a column-type container to easily asses the translocation of compounds through the barrier layer. The researchers used various methods to confirm the barrier integrity and maturation levels of the plane organoids and to ensure the robustness of the system. Their analysis also showed that the model could be used to assess how well different compounds could cross the barrier, specifically by examining the permeability coefficients.

Implications for Drug Development and Placental Biology

“Using the organoids as a model of the placental barrier will help scientists better understand general placental biology and potential drug toxicity,” says Dr. Hori. “We also designed our model in a manner such that the cells could be easily cultured and it could be evaluated using microscopic observation.”

The TS cell-based organoid model generated in this study effectively addresses many of the difficulties that have previously hampered laboratory-based assessments of placental physiology. It will be a useful tool for not only elucidating details of the development of this organ, but also for evaluating the transfer rates and toxicity levels of various compounds. This will be critical in the drug development process to avoid damaging the placenta or harming the fetus.

Reference: “Trophoblast stem cell-based organoid models of the human placental barrier” by Takeshi Hori, Hiroaki Okae, Shun Shibata, Norio Kobayashi, Eri H. Kobayashi, Akira Oike, Asato Sekiya, Takahiro Arima and Hirokazu Kaji, 8 February 2024, Nature Communications.
DOI: 10.1038/s41467-024-45279-y