Organoids made from amniotic fluid will tell us how fetuses develop
As a fetus grows in the womb, it sheds cells into the amniotic fluid surrounding and protecting it. Now researchers have demonstrated that they can use those cells to grow organoids, three-dimensional structures that have some of the properties of human organs-in this case kidneys, small intestines, and lungs. These organoids could give doctors even more information about how fetal organs are developing, potentially enhancing prenatal diagnoses of conditions like spina bifida.
These aren't the first organoids produced from fetal cells. Other groups have grown them from discarded fetal tissue. But this group is among the first to grow organoids from cells taken from amniotic fluid, which can be extracted without harming the fetus.
The entire concept is really groundbreaking," says Oren Pleniceanu, a stem cell biologist and head of the Kidney Research Center at Sheba Medical Center and Tel-Aviv University who has also been working on organoids from amniotic fluid. This ability to get fetal cells from the amniotic fluid, it's like a free biopsy," he says. But he points out that there's still room for improvement when it comes to describing the cells that are present. It's not that easy to define which cells these are," he says.
Researchers have known for decades that amniotic fluid holds fetal cells. That's what allows doctors to diagnose conditions like Down syndrome and sickle-cell disease before birth via amniocentesis, in which a needle is used to take a sample of the fluid. The vast majority of these cells, 95% or more, are dead cells sloughed off by the fetus, says Mattia Gerli, a stem cell biologist at University College London and an author of a paper on the work published in Nature Medicine today. But what the researchers homed in on was the much smaller fraction of live cells in amniotic fluid.
First, they worked to determine what kinds of cells were there, mapping their identities and then using single-cell sequencing to assess where they originated. Next, the team placed three kinds of progenitor cells-kidney, lung, and small intestine-in a 3D culture to see if they would form organoids.
We're just taking them as they are and putting them into a droplet of gel. This is very low tech," coauthor Paolo De Coppi, a pediatric surgeon at University College London and the Great Ormond Street Hospital, said in a press briefing.
It worked. The organoids grew, and they developed features of the tissue that the cells came from. Within weeks the lung organoids, for example, had beating, hairlike structures called cilia, like those found inside the lung.
As a pediatric surgeon, De Coppi often deals with congenital birth defects. Doctors can spot these defects using imaging, but they don't have a good way to assess their severity or how they affect organ function. To look at whether their lung organoids might be able to provide some of that information, the team collected cells from fetuses with a rare condition called congenital diaphragmatic hernia (CDH). These fetuses have a gap in their diaphragm that allows organs from the abdomen to push up into the chest cavity and compress the lungs. If the lung is being compressed, the lung doesn't develop in the way it should," De Coppi says. So only 70% of these fetuses will survive."
The team compared organoids grown from CDH fetuses with organoids grown from healthy fetuses. Initially both organoids looked the same. But when the researchers pushed them to differentiate to mimic the part of the lung closest to the windpipe, or the deeper portions of the lung, they saw some striking differences. Both healthy and CDH organoids developed cilia, but the pattern was different in CDH organoids, and they struggled more to differentiate. The CDH organoids also produced less surfactant, a substance that helps the air sacs in the lungs function properly.
CDH can be treated: surgeons place a balloon in the windpipe of the fetus to force the lungs to push back against the encroaching organs. When the researchers compared lung organoids grown from cells taken from amniotic fluid before and after the balloon procedure, they found that the treated organoids grew more like normal lung organoids, and their gene expression suggested that they were more developed.
These results point to two possible uses. Placing the balloon requires fetal surgery, and doctors don't have a good way to figure out which fetuses might benefit and which will not. These personalized organoids might help them determine how underdeveloped the lungs are so they can make a more informed decision. And for those fetuses that undergo the procedure, the organoids could give doctors information about whether it worked.
These researchers aren't the only ones to develop organoids from cells in amniotic fluid. In a preprint posted in October 2023, Pleniceanu and his colleagues report that they too managed to culture such cells into lung and kidney organoids. But rather than growing their organoids in a generic growing medium, they developing mediums that are designed to promote the growth of specific organoids-for example, one medium might enhance the growth of kidney organoids, another might prompt the development lung organoids.
Organoids are not, as their name suggests, miniature functioning organs. But these collections of cells do re-create some of the structure and complexity of organs. As a result, they can offer a unique window into human development. And because they carry the same genetic mutations as the fetus, they can also give doctors a peek at how that particular fetus is developing.
Organoids aren't ready for the clinic yet, but the two teams envision many uses for these personalized fetal organ models. When an ultrasound detects some abnormality, organoids could reveal the underlying cause in real time, and perhaps point doctors to therapies that could be delivered while the organs are still developing. You might be able to intervene, even before birth, which is pretty amazing," Pleniceanu says. These organoids could also help researchers better understand abnormalities that aren't the result of a genetic disorder and shed light on how environmental exposures affect development.
De Coppi points out that the pharmaceutical industry has begun using organoids derived from adult cells to identify new therapies. Now there's the possibility of bringing those technological developments back into fetal development, he says, because for the first time, we can actually access the fetus without touching the fetus."
Update 3/4: This story has been updated with comments from Pleniceanu.