July 11, 2023 | Recent research is harnessing the potential of placenta, brain, ovarian, and heart organoids and organ-on-a-chip devices to glean valuable insights about reproductive health, the processes involved in pregnancy, and early growth and development.
These emerging findings are deepening our understanding of crucial processes and could eventually lead to new ways of preventing, diagnosing, or treating various reproductive system issues such as infertility, preterm birth, or ovarian cancer.
Placenta Organoids and Placentas-on-a-Chip Address Pregnancy Unknowns
The formation of the placenta and its embedding into the uterus is essential for a healthy pregnancy, and learning more about this temporary organ could help answer key questions about issues like miscarriages, stillbirth, and pre-eclampsia.
A paper published in Nature (DOI: 10.1038/s41586-023-05869-0) details the work of researchers who have applied single-cell genomics and spatial transcriptomics to a set of samples to examine the early stages of placental development and gain a better sense of how the placenta and uterus interact with one another.
As the placenta develops, it forms structures that attach to the uterus, and the outer layer of cells (trophoblast) travel through the uterine wall, altering maternal blood vessels to provide nutrients. The international group spanning the UK, Germany, and Switzerland gained insight into trophoblast development, suggesting what may go wrong in disease and detailing the involvement of various populations of cells.
They also compared their results to placental trophoblast organoids grown in the lab. They learned that most of the cells identified in tissue samples can be observed in organoid models, although some later populations of trophoblast are not seen and are thought to form in the uterus after receiving signals from maternal cells. This work has led to the creation of an open-access cell atlas that can inform future research. “Insights from our research show that our previous understanding of placental implantation was incomplete and that the maternal uterine cells release communication signals to encourage placental growth,” Roser Vento-Tormo of the Wellcome Sanger Institute said in a news release.
Placenta as Barrier, Pathway
A group of Florida Atlantic University researchers is learning more about the inner workings of placental malaria (PM), malaria during pregnancy in which Plasmodium-infected red blood cells accumulate in the placental intervillous space, which causes up to 200,000 newborn deaths every year. They have built a placenta-on-a-chip model to mimic the nutrient exchange that takes place between fetus and mother during this illness.
The findings appeared in a Scientific Reports paper (DOI: 10.1038/s41598-022-19422-y) and revealed that chondroitin sulfate A binding infected erythrocytes “added resistance to the simulated placental barrier for glucose perfusion and decreased the glucose transfer across this barrier.” The researchers indicated that their results could advance our understanding of the pathology involved with this illness and contribute to developing models useful for studying possible PM treatments.
In other work, a group of researchers at the University of Texas Medical Branch have come up with a method for examining gestational disease using mini-organ models that mimic pregnancy. The group developed two organ-on-a-chip devices that represent the fetal membrane and placenta and used them to test the efficacy of drugs during pregnancy. Their findings, published in Lab on a Chip (DOI: 10.1039/D2LC00691J), revealed that statin drugs reduce the amount of inflammation caused by infection or oxidative stress during pregnancy. Scientists hope to discover effective treatments considering this inflammation can contribute to preterm births.
Meanwhile, German biotech and pharmaceutical giant Bayer has announced a year-long pilot to predict whether small molecules can cross the blood-placenta barrier in pregnant women. The project will involve an organ-on-a-chip that represents human tissues involved in drug disposition along with a pumping system. Collaborators include esqLABS, Dynamic42, and the Placenta Lab of Jena University Hospital.
Brain Organoids Used to Study Various Conditions, Possible Treatments
Several studies appearing in Molecular Psychiatry have used brain organoids to explore conditions such as fetal alcohol syndrome, autism spectrum disorder, and pediatric bipolar disorder.
Researchers at the University of California San Diego School of Medicine have learned more about the impact of prenatal alcohol exposure, for example, which can lead to growth deficits, physical differences, or brain damage. Alysson Muotri and colleagues carried out their study (DOI: 10.1038/s41380-022-01862-7) by exposing human brain organoids to alcohol and then looking for changes. Their work reveals how alcohol exposure impacts the development of new brain cells and the way they function.
“There are several alterations that we notice—some at the molecular level,” Muotri, a professor in the Departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine, told Diagnostics World.
There are a set of genes and molecular pathways inside of the cell that changes, for example, and analyzing the impact of alcohol exposure a bit later on revealed that the cell populations in these brain organoids have changed as well. Examining the functional level revealed that networks suffer some alterations, too.
The last piece of their exploration involved determining if something could be done about these types of alterations, so the researchers screened novel therapeutics to offset the changes caused by early alcohol exposure. They found a couple of drugs that may work, he said, so these are possible candidates for a clinical trial.
However, there are a variety of caveats that are intrinsic to the model used to conduct this research. “There are orders of magnitude in scale,” Muotri pointed out. “We’re talking about 5 million cells; the human brain has 86 billion cells.” He also acknowledged that when a mother ingests alcohol, it passes through her blood, metabolizes, and then reaches the fetus. With this organoid-based research, on the other hand, there is no body involved and the brain cells are directly exposed. Moving forward, Muotri intends to build upon this work by searching for the most critical circuitries affected by alcohol exposure and exploring questions related to acute versus chronic alcohol exposure.
Maternal immune activation (MIA) during essential parts of gestation is associated with neurodevelopmental issues in offspring, researchers at the University of Tübingen’s Hertie Institute for Clinical Brain Research in Germany have pointed out. To explore further, they developed a human brain organoid model of MIA that can be used to study the mechanisms underlying the heightened risk of developing various disorders, including autism spectrum disorder.
“By establishing a human 3D model of the cytokine-mediated effects of MIA on human neocortical development, we close the gap between human epidemiological studies and mechanistic studies in animal models,” the researchers noted in their study (DOI: 10.1038/s41380-023-01997-1).
Exploring the biology underlying psychiatric disorders is a tall order, at least in part because scientists cannot easily gather brain cells from living humans to study in the lab. But University of Utah Health researchers have shown that organoids can help. A team of neurobiologists, radiologists, geneticists, and psychiatrists combined imaging data with an analysis of patient cells at the molecular level. Their findings (DOI: 10.1038/s41380-023-02035-w) suggest that changes in the brain seen in individuals with pediatric bipolar disorder might all tie into a specific gene.
Using blood cells donated by a child with bipolar disorder, the parents, and a sibling, the researchers converted them into induced pluripotent stem cells, brain cells, and ultimately brain-derived organoids. The organoids enabled the research group to model particular developmental stages associated with specific brain regions, Alex Shcheglovitov, an assistant professor of neurobiology at the University of Utah, said in a news release. In this scenario, the organoids resemble the frontal portion of the human fetal brain.
The group ran experiments to figure out how cells from the child with bipolar disorder were different from the cells of other (unaffected) family members and discovered a mutation in the PLXNB1 gene. They also found that neurites, which typically make crucial connections with nearby cells, were shorter but that adding normal PLXNB1 to the patient’s cells led to normal growth.
Interestingly, Shcheglovitov told Diagnostics World, “PLXNB1 is an important regulator of several signaling cascades.” He also found it intriguing that some of the signaling cascades downstream of PLXNB1 have been associated with bipolar disorder in prior studies, which suggests that this pathway could be explored as a target for this pediatric disorder. “But this is just speculation,” he said, “and more work has to be done to test this.”
Ovarian Organoids Support Research and Drug Development Efforts
In collaboration with New York-based biotech company Gameto, a group of Harvard and Duke University researchers has developed a human ovarian organoid that can be used for research and drug development. The technology could help lead to treatments for female reproductive system issues like ovarian cancer or infertility.
Scientists have previously developed artificial ovaries in lab settings using stem cells from mice embryos. The approach has also been used with human induced pluripotent stem cells (iPSCs), and although this has led to the production of human germ cells, creating human granulosa cells has proven to be a loftier challenge.
In their study, the researchers demonstrate that activating a certain set of proteins that switch genes on or off in iPSCs can get them to morph into granulosa cells. The ovaroids—ovarian organoids—are detailed in a paper published in eLife (DOI: 10.7554/eLife.83291). The work establishes a method for the creation of granulosa-like cells that express granulosa marker genes and have similar transcriptomes to the human fetal ovary.
This efficient production of human ovaroids is “a feat in and of itself,” senior author George Church, professor of genetics at Harvard Medical School and faculty member at the Wyss Institute, said in a news release. But doing so in five days rather than the month it takes using human/mouse hybrid ovaroids is expected to “dramatically speed up the discovery of critical information about women’s health and reproduction.”
Meanwhile, researchers from Denmark and Finland have detailed a method for the creation and expansion of organoids geared toward high-grade serous ovarian cancer (HGSC). In a paper published in Developmental Cell (DOI: 10.1016/j.devcel.2023.04.012), they indicated that their resource “facilitates the application of HGSC organoids in basic and translational ovarian cancer research.”
Heart Organoids Could Pave the Way Toward New Treatment Approaches
At the Technical University of Munich’s Center for Organoid Systems, a team led by Alessandra Moretti, professor of regenerative medicine in cardiovascular disease, has created an organoid that mimics the development of the human heart. There are reasons why our understanding of the heart is limited. Findings from animal research do not fully translate to the human organ, for example, and the human heart begins to form when women may be unaware of their pregnancy.
Moretti and colleagues believe organoids could help us arrive at a deeper understanding of the heart and make it possible to study its early development. Their organoids do not pump blood but can contract like heart chambers. They include both heart muscle cells (cardiomyocytes) and cells of the heart wall’s outer layer (epicardium)—a combination the researchers say is a first of its kind.
According to Anna Meier, the study’s first author, epicardium cells are crucial for learning how the heart is formed. Other cell types in this organ are formed from these cells, she said in a news release, and the epicardium also plays a central role in creating the heart’s chambers. The researchers reported their initial discoveries in a Nature Biotechnology paper (DOI: 10.1038/s41587-023-01718-7). They found, for example, that precursor cells of a type that have only recently been discovered in mice are formed at about the seventh day of the organoid’s development.
Their work may help arrive at a better understanding of why the fetal heart can repair itself—an ability that is lacking in human adult hearts. The hope is that this could, in turn, lead to new treatment approaches for heart attacks and other heart-related conditions.
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Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.