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Microscopy image of Kidney amniotic fluid organoids resembling renal tubules.

An kidney organoid made from amniotic cells Credit: Giuseppe Calà, Paolo De Coppi and Mattia Gerli

Cells taken from the fluid around growing fetuses have been used to make organoids, 3D bundles of cells that mimic tissue. These organoids could help researchers to understand diseases that develop in the fetus during pregnancy.

The researchers grew organoids from lung, kidney and small intestine cells shed into amniotic fluid collected from 12 pregnancies between the 16th and 34th weeks of gestation. This is the first time that organoids have been grown directly from cells taken from ongoing pregnancies, says Mattia Gerli, a stem-cell biologist at University College London and a co-author of the study, which is published in Nature Medicine1.

Around 13,000 children in the United Kingdom were born with at least one congenital anomaly in 2020, out of nearly 600,000 births. The authors hope that the organoids could one day provide information about how congenital conditions progress, and even be used to personalize treatment for individual fetuses in future.

Organoids are usually grown from cells taken from biopsies, which are then programmed into induced pluripotent stem cells, which are mature cells that are reprogrammed so they can differentiate into any type of cell. The technique can produce complex structures but takes a long time. Many tissue types have now been studied by means of organoids, including the brain, heart and retina. The organoids are used to model how the tissue functions and reacts in response to drugs and diseases.

But modelling fetal tissue in this way remains challenging because researchers have limited access to the necessary cells. One option is to use tissue taken from terminated pregnancies, but this is limited to earlier stages of gestation and is accompanied by ethical issues. In the latest study, the researchers instead used amniotic fluid as a source of living cells, shed as the fluid surrounds and supports the growing fetus. This allows the researchers to study fetal tissue at later stages of development.

Fluid extraction

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Samples were obtained either through amniocentesis — which involves a needle being inserted into the womb and removing amniotic fluid, and is usually performed at up to 20 weeks of gestation — or through amniotic drainage to remove excess fluid, at up to 34 weeks’ gestation. These are standard procedures during prenatal care, so “they give us the opportunity to take amniotic fluid without any additional procedure”, says study co-author Paolo De Coppi, a paediatric surgeon at Great Ormond Street Hospital in London. All samples were taken from people who were undergoing one of the procedures independent of the study.

The researchers first isolated individual cells from the samples and characterized their origins. Most were from the epithelial layer — the layer of cells that covers an organ’s surfaces. Epithelial cells “naturally come together and assemble”, making them ideal for forming organoids, says Benoit Bruneau, a researcher of paediatric heart disease at the Gladstone Institute of Cardiovascular Disease in San Francisco, California. “A lot of congenital diseases involve the epithelial tissues,” says Gerli, so the resulting organoids are relevant for studying such conditions.

The team grew organoids from three organs — the small intestines, kidneys and lungs. The cells were transferred into a gel medium to multiply and grow. Each organoid expressed the genes and proteins of the organ it originated from.

Alongside the tissue-like organoids, the researchers also modelled congenital diaphragmatic hernia (CDH), a disorder where the diaphragm fails to develop correctly, using cells from samples affected by the disorder.

Unlike organoids made from pluripotent stem cells, the amniotic fluid cells already have an organ identity. “There is no reprogramming, no manipulation,” says Gerli, “we’re just allowing the cells to express their potential.” This makes future applications in clinic more feasible, he adds. The relatively simple techniques also cut the time needed to grow the organoids to just four to six weeks, from the five to nine months typically needed when stem cells are used.

Future possibilities

The research isn’t ready to transfer to the clinic yet, the authors say. Organoids grown from amniocentesis could perhaps be used to screen treatments. At the moment, only epithelial tissue from the three organs has been successfully grown into organoids using this technique. More complex congenital disorders probably affect multiple tissue layers, such as mesenchymal cells, another type of cell found in several organs. And it might not be possible to use the method to model organs that don’t shed cells into the amniotic fluid, such as the brain or the heart, says Bruneau, who studies the most common congenital disorder — heart defects.

“The question is, how faithfully do these organoids reveal the underpinnings of the disease and how useful are they for not just modelling, but for drug testing?” says Bruneau. Their capabilities will have to be compared with those of organoids derived from biopsies or pluripotent stem cells, in terms of the level of responsiveness to drugs, says Núria Montserrat, who studies organ regeneration at the Institute for Bioengineering of Catalonia in Barcelona, Spain.

Gerli says that the next steps are to test the capabilities of the CDH organoids for modelling the disease. Comparisons to patient data will be needed to work out how characteristics of the disease are reflected in the gene and protein expression of the organoids. This will begin to answer questions about their usefulness. “We hope this just opens up to more research by us and others,” says De Coppi.

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