‘Mini lungs’ from amniotic fluid cells predict the success of lung surgery in foetus

The amniotic fluid of a pregnant woman contains millions of cells of the foetus. These originate from, for example, the skin or intestines of the unborn baby. Most of the amniotic fluid cells come from the foetus's lungs and kidneys. When an ultrasound suggests a congenital abnormality, the doctor usually offers amniocentesis. Today, those cells from the amniotic fluid are tested for the presence of genetic abnormalities. Researchers from KU Leuven, UZ Leuven and the Great Ormond Street Hospital for Sick Children in London have now shown that amniotic flud cells can also be used to predict the function of organs after birth.  

The researchers used the cells from the amniotic fluid to turn them into three-dimensional cell cultures, also called organoids, in a culture dish. Organoïds are a type of mini-organs that can both mimic the structure and function of the organs they originate from. Organoids from children and adults are already used today in laboratories as models to mimic disease processes, better understand them and test treatments on them. Now, organoids were made from foetal cells in the amniotic fluid. This was done for the first time in a direct manner, i.e. without reprogramming the cells.

The work published in Nature Medicine confirms the researchers' hypothesis that foetus-derived cells apparently still have the power to transform themselves into mini-organs that can mimic both the structure and function of the original organs. They were able to demonstrate this for foetal cells derived from the kidneys, intestines and, in particular, the lungs.

Prenatal test for organ functions of the foetus

In a next step, the researchers cultured lung organoids from the amniotic fluid of foetuses that had abnormally small lungs due to a diaphragmatic defect (hernia diaphragmatica). A diaphragmatic defect is fatal in one in three babies with that congenital disorder. Today, doctors predict the course of the condition after birth by measuring the size of the lungs. The now-published study shows that cultured lung organoids from the amniotic fluid mimic the congenital defect.  What's more: the organoids also seemed to mimic the severity of the disorder. If these findings can be confirmed in larger groups of patients, it means that doctors would have a prenatal test to predict specific organ functions in an unborn baby for the first time. Furthermore, the researchers also want to use the organoids to test out medication even before birth, for example, so that the baby can quickly receive the most effective medication after birth. 

Prof. dr. Jan Deprest, foetal surgeon at UZ Leuven: “With the organoids from the amniotic fluid, we can look into a culture dish how the cells of an unborn baby will react after birth. This is very useful information for parents of an unborn baby with a lung disorder. Twenty weeks before birth we can predict the baby's lung function. We could already estimate how the blig the lungs would be by measuring them. Now we can also predict how the lungs will be behave after birth and therefore decide how serious the lung disorder will be. This is a decisive factor when decisions have to be made by parents. E.g. whether it is useful to operate in the uterus, which is always a risk. Thanks to the ability to test drugs on cultured organoids, it is also possible to start research into an treatment with medication for babies with underdeveloped lungs."

Prof. dr. Mattia Gerli, professor stem cell sciences and senior author of the study (University College London): “The organoids we cultured from amniotic fluid cells exhibit a number of functions of the tissues from which they were derived, for example in terms of gene and protein expression. As a result we can study what happens during the development of the foetus for the first time, and this in both healthy and sick babies. We actually know very little about the later stages of human pregnancy, so it is incredibly exciting to explore new areas of prenatal medicine.”

Prof. dr. Paolo de Coppi, paediatric surgeon (Great Ormond Street Hospital for Children): “This discovery is an enormous step forwards in foetal medicine. A diagnosis is normally made on the basis of MRI images, an ultrasound or genetic analysis. For doctors it is often difficult to communicate something to parents of an unborn child with a disorder about the chances of surgery or treatment. This remains difficult to this day, but the possibility to study prenatal organoids functionally, is a first step towards a more detailed prognosis in the future and hopefully towards more successful treatments.”

The study Single cell-guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids is published in Nature Medicine.

About the research group

The specific interest in congenital lung defects and the possibility of accurately predicting its function before birth is in line with a spearhead of the foetal surgery research group at UZ Leuven. Indeed, the university hospital has developed a surgical technique to accelerate the growth of the lungs even before birth in foetuses with diaphragm defects and very small lungs. Just last year, researchers showed that such foetal surgery doubles the baby's chances of survival. Since there are also side effects, any new method that can more accurately predict the expected outcome is welcome.

The collaboration between KU Leuven, UZ Leuven and the research group at Great Ormond Street Hospital has been going for six years. The groups have a clinical foetal surgery programme in both Leuven and London, but also a substantial research programme. London researchers were also previously the first to isolate stem cells from human amniotic fluid and grow them in a reproducible manner.

Caution A breakthrough in research is not the same as a breakthrough in clinical medicine. This study is a proof-of-concept with promising results, but more research will be needed before this discovery can be integrated into daily hospital practice.