Organoids to Study Rare Diseases Derived from Amniotic Fluid

Studying fetal development with amniotic fluid-derived organoids

Researchers have made a breakthrough in studying fetal development by successfully growing organoids, 3D cell structures mimicking tissues, from cells found in amniotic fluid. This fluid surrounds and protects the developing fetus during pregnancy.

This is the first time scientists were able to grow organoids directly from cells collected during ongoing pregnancies (between 16th and 34th week). This achievement, led by stem cell biologist Mattia Gerli from University College London, is published in Nature Medicine.

The research holds promise for improving our understanding of congenital anomalies, birth defects affecting nearly 13,000 newborns in the UK annually. The scientists believe these organoids could eventually provide insights into how these conditions develop and potentially pave the way for personalized fetal treatment in the future.

Traditionally, organoids are grown from cells obtained through biopsies, then reprogrammed into versatile induced pluripotent stem cells. While this method allows for complex structures, it is time-consuming. Researchers have already used organoids to study various tissues, including the brain, heart, and retina, to understand their function and response to drugs and diseases.

However, studying fetal tissue using this approach is challenging due to limited access to suitable cells. One option involves using tissue from terminated pregnancies, which raises ethical concerns and restricts access to later developmental stages. The new study overcomes this limitation by utilizing readily available amniotic fluid, offering a valuable source of living fetal cells for research at later pregnancy stages.

Acquiring and isolating cells from amniotic fluid

The researchers obtained amniotic fluid samples through two established prenatal procedures: amniocentesis (before 20 weeks) and amniotic drainage (up to 34 weeks). These procedures are routinely performed during pregnancy, minimizing additional burden on participants. Co-author Paolo De Coppi, a pediatric surgeon, emphasizes the ethical consideration: “they give us the opportunity to take amniotic fluid without any additional procedure.”

Once obtained, the team isolated and analyzed individual cells within the samples. Most originated from the epithelial layer, which forms the outer surface of organs. Benoit Bruneau, a researcher specializing in pediatric heart disease, explains the suitability of these cells: “Epithelial cells naturally come together and assemble,” making them ideal for forming organoid structures. Additionally, as Gerli points out, “a lot of congenital diseases involve the epithelial tissues,” highlighting the relevance of these organoids for studying various birth defects.

Growing organoids and modeling disease

The research focused on three specific organs: the small intestines, kidneys, and lungs. By placing the isolated cells in a gel medium, the researchers facilitated their growth and multiplication. Notably, each resulting organoid expressed genes and proteins characteristic of its corresponding organ, demonstrating successful tissue development.

In addition to these tissue-like organoids, the researchers took another step by modeling congenital diaphragmatic hernia (CDH) using cells from affected samples. This specific disorder involves a malformation of the diaphragm.

A crucial advantage of this approach lies in the inherent nature of amniotic fluid cells. Unlike those derived from pluripotent stem cells, which require reprogramming, these cells already possess an intrinsic organ identity. Gerli emphasizes this benefit: “There is no reprogramming, no manipulation,” highlighting the simpler and potentially more ethically sound approach. He further adds that this characteristic simplifies future clinical applications. Moreover, the relatively straightforward techniques significantly reduce the growth time of organoids, taking only four to six weeks compared to the five to nine months required for stem cell-derived organoids.

Challenges and next steps

While the study holds promise, the authors acknowledge its limitations and the need for further research before clinical applications become feasible.

One potential application is using organoids derived from amniocentesis for treatment screening. However, the current success is limited to epithelial tissues from the three studied organs. More intricate congenital disorders likely involve multiple tissue layers, including mesenchymal cells, which are not yet captured by this method. Additionally, organs like the brain and heart, which don’t shed cells into the amniotic fluid, might not be suitable for this approach, as highlighted by Bruneau, a researcher specializing in heart defects, the most common congenital anomaly.

Bruneau raises crucial questions about the fidelity of these organoids in reflecting disease mechanisms and their potential beyond just modeling to encompass drug testing. He emphasizes the need to compare their capabilities with organoids derived from biopsies or stem cells, particularly regarding their responsiveness to drugs.

Núria Montserrat, a researcher studying organ regeneration, further emphasizes the need to evaluate the organoids’ usefulness by comparing their gene and protein expression with patient data. This comparison will shed light on how effectively these organoids mirror the characteristics of the disease being modeled.

The authors, including Gerli and De Coppi, acknowledge the need for further research to explore the full potential of this method. They aim to test the capabilities of the CDH organoids in accurately modeling the disease and hope their findings will pave the way for further investigation by themselves and other researchers.

Resources

1. ^JOURNAL Tozer, L. (2024). Organoids grown from amniotic fluid could shed light on rare diseases. Nature. [Nature]
2. ^JOURNAL Gerli, M. F. M., Calà, G., Beesley, M. A., Sina, B., Tullie, L., Sun, K. Y., … De Coppi, P. (2024). Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids. Nature Medicine. [Nature Medicine]

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