\n<\/p>\n
In 2017, Ashley Moffett, a reproductive immunologist, walked to the pharmacy near her laboratory at the University of Cambridge, UK, to buy a pregnancy test. But it wasn\u2019t for Moffett. Her postdoc, Margherita Turco, had created what she thought might be the first cluster of cells capable of mimicking the tissue of the placenta \u2014 a placental organoid. But she needed a way to be sure.<\/p>\n
\u201cWe must do a pregnancy test on them,\u201d Moffett said.<\/p>\n
If Turco was correct, the miniature ball of cells she had created would secrete HCG, the hormone that triggers a positive pregnancy test. \u201cI took the stick, put it in, and it was positive,\u201d says Turco, now a reproductive biologist at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. \u201cIt was the best celebration.\u201d<\/p>\n
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Scientists make organoids such as this by coaxing stem cells to grow in a jelly-like substance and to self-assemble into clumps of tissue. The typically hollow or solid balls of cells don\u2019t look anything like real organs. But they do take on key aspects of the organ that they\u2019re meant to represent \u2014 liver, brain, lung or stomach, for instance.<\/p>\n
The mini-organs have the advantage of being more realistic than a 2D cell culture \u2014 the conventional in vitro workhorses \u2014 because they behave more like tissue. The cells divide, differentiate, communicate, respond to their environment and, just like in a real organ, die. And, because they contain human cells, they can be more representative than many animal models. \u201cAnimals are good models in the generalities, but they start to fall down in the particulars,\u201d says Linda Griffith, a biological engineer at the Massachusetts Institute of Technology in Cambridge.<\/p>\n
Over the past decade, organoid research has exploded. Researchers have used them to study early brain development, test cancer therapies and much more. And these 3D models stand to become even more crucial as US agencies, including the National Institutes of Health, the Food and Drug Administration and the Environmental Protection Agency, aim to move away from animal testing.<\/p>\n
Now researchers are using organoids to study female reproduction, an area in which animal models can be especially limited. Lab mice, for example, don\u2019t menstruate. And their placentas don\u2019t develop in the same way as human placentas do. That challenge, along with a historical lack of funding for women\u2019s health research, has left basic questions unanswered.<\/p>\n
\u201cI really see it as a powerful model to do science,\u201d says Mirjana Kessler, a cell biologist at the Ludwig Maximilian University of Munich in Germany, who has developed an organoid that mimics the fallopian tube and a biobank of ovarian cancer organoids.<\/p>\n
Organoids of the placenta, endometrium, ovary and vagina could help to reveal how these organs function, and what happens when things go awry.<\/p>\n
\u201cThere\u2019s so much work to do to understand the normal biology,\u201d Turco says.<\/p>\n
The placenta plays a key part in maternal health during pregnancy. Humans aren\u2019t the only species that develops a placenta, but the \u201chuman placenta is quite different than most other species, even primates actually, apart from apes\u201d, says Moffett. Mice and humans, for example, both have placentas that invade the uterine lining, but the timing of development and the depth of invasion differ. Exactly what happens during the early days of placental development is still unclear, but problems at this stage can have serious consequences later.<\/p>\n
One of the placenta\u2019s first jobs is to create a link between the mother and the developing embryo. To do this, the placenta invades the spiral arteries that feed the uterus. The invasive cells open up the arteries, \u201cessentially making a channel so that mom can provide what she needs through her blood supply\u201d, says Victoria Roberts, a developmental biologist at the Oregon National Primate Research Center in Beaverton. (Nature recognizes that transgender men and non-binary people might have female reproductive organs and might become pregnant. \u2018Mother\u2019 is used in this article to reflect language used by the field.)<\/p>\n
The process can be deadly if it goes wrong. If the placenta invades too deeply, a condition called placenta accreta, the expectant mother can lose too much blood during birth. And if the organ doesn\u2019t invade deeply enough, then the fetus might not get enough nutrients to sustain its growth.<\/p>\n
Organoids made of placental cells can help reveal how the organ invades the uterine lining.<\/p>\n
Turco lab, Friedrich Miescher Institute for Biomedical Research<\/p>\n
Shallow invasion can also impact the mother\u2019s health. When the placenta doesn\u2019t get enough blood, research suggests it can become inflamed and secrete harmful factors into the mother\u2019s blood that trigger pre-eclampsia, a condition characterized by protein build-up in the blood and dangerously high blood pressure. Worldwide, 2\u20138% of pregnant people develop the condition. \u201cIt\u2019s a very serious pregnancy complication that goes silent and undetected until very late into pregnancy,\u201d says Quinton Smith, a chemical engineer at the University of California, Irvine. The only way to cure the condition is to deliver the baby, even if that means a preterm birth.<\/p>\n
To better understand the condition, Smith, Turco and other researchers are using organoids made of placental cells called trophoblasts to model the molecular processes involved. Turco is focused on the basic biology of how invasion is regulated, a process that seems to be controlled by both the fetus and the mother. \u201cIt\u2019s got to be a compromise,\u201d Moffett says. \u201cIt\u2019s an absolute dialogue.\u201d<\/p>\n
That dialogue seems to be happening between the placenta and the uterine lining. As a case in point, when an embryo implants somewhere the lining doesn\u2019t exist \u2014 on a scar left by a previous caesarean delivery or in a fallopian tube, for example \u2014 \u201cthere\u2019s no control of the invasion at all\u201d, Turco says.<\/p>\n
Research suggests that immune cells called uterine natural killer cells have a key role in this conversation. The cells don\u2019t kill but instead send out chemical signals that help to regulate the invasion of the uterine lining.<\/p>\n
When Turco, Moffett and their colleagues exposed the mini-placentas to these chemical signals and analysed which genes the cells expressed, they found that many were associated with pre-eclampsia.<\/p>\n
\u201cI\u2019m sure it\u2019s not the whole story,\u201d Moffett says. \u201cBut it does show you how you can use those organoids to ask these fundamental questions about human pregnancy.\u201d<\/p>\n
Turco\u2019s first attempt to create a mini-placenta in 2016 didn\u2019t go as planned. The placental tissue she was working with contained not only trophoblasts, but also a few rogue maternal cells from the endometrium, the uterine lining that builds up and then sheds each month during menstruation. Those maternal cells \u201ckept on growing and taking over,\u201d she says. \u201cIt was a setback at that time.\u201d<\/p>\n
But now Turco sees it as a wonderful discovery, because she instead grew organoids that represent the endometrium. This, along with another endometrial model published in the same year, really opened the door for everyone else, says Griffith.<\/p>\n
Griffith has been studying the endometrium for more than a decade. The research is personal. When Griffith hit puberty, she developed a debilitating condition called endometriosis. The disease, which affects about 10% of people with a uterus who are of reproductive age, occurs when endometrium-like tissue grows in places it doesn\u2019t belong.<\/p>\n
Because this tissue is trapped inside the body, it can\u2019t be shed properly. Instead, it can irritate surrounding healthy tissue, causing inflammation, pain and scar tissue. Although existing therapies address some of the symptoms, they don\u2019t provide a cure.<\/p>\n
Organoids are typically grown in Matrigel, a jelly-like substance extracted from mouse tumour cells that allows the cells to assemble into 3D structures. Griffith wanted to put epithelial cells, which compose the uterine lining, with stromal cells that support that lining. In the body, these cells need to communicate with each other to bring about the changes that occur with the monthly cycle. But Matrigel is packed with proteins that can hamper the cell-to-cell communication. So Griffith and her colleagues developed a hydrogel that\u2019s entirely synthetic.<\/p>\n
Griffith\u2019s team has also been working on the next step, a model of abnormal endometrial tissue that the researchers can use to test therapies for the condition. Because blood vessels are crucial to maintaining this tissue, Griffith knew she wanted to include them. To do this, she and her colleagues placed the organoid on a microfluidic chip surrounded by cells that form blood vessels. \u201cWe put all of these cells in together at the beginning in a gel, and the blood vessels form spontaneously,\u201d she says. \u201cSo the organoids turn into lesion-like structures,\u201d she adds. \u201cIt\u2019s actually kind of wild.\u201d<\/p>\n
Griffith and her team have created these model systems from the cells of about a dozen people with endometriosis, and they\u2019re beginning to use them to test compounds that could be promising therapies for the condition.<\/p>\n
Turco, meanwhile, has developed her endometrial organoid into a model of menstruation. Her team treated the endometrial organoids with hormones to mimic what happens when the endometrial lining is regenerating. Then the researchers stopped the hormones to mimic the start of menstruation. In the uterus, the lining breaks up naturally. In the model, however, the researchers break the organoids up mechanically. When the cells are put back into a gel, the organoids reform. \u201cAnd you can keep doing this over and over again,\u201d she says.<\/p>\n
The model allows them to study the mechanisms at work during regeneration. \u201cThat\u2019s not possible to study in humans \u2014 like ever,\u201d Turco says. Researchers have long thought that the stem cells that lie beneath the surface of the lining are solely responsible for regenerating it. But Turco\u2019s research suggests that cells on the surface might have a role, too.<\/p>\n
For Kathryn Patras, a microbiologist at Baylor College of Medicine in Houston, Texas, organoids are a way to explore the diversity of bacteria that colonize the vagina and how they influence human health. A healthy vaginal microbiome can help to prevent harmful bacteria from taking over. A disrupted microbiome, however, seems to increase a woman\u2019s risk of catching a sexually transmitted infection and of experiencing complications during pregnancy.<\/p>\n
The vaginal microbiome is particularly tricky to study in mice. Its composition is entirely different from that of humans. And introducing a human microbiome into the mouse vagina is nearly impossible. Patras tried for years. \u201cIt just failed splendidly,\u201d she says.<\/p>\n
So Patras and her colleagues harvest naturally existing stem cells from the human vagina and coax these cells to form organoids. These mini-vaginas are hollow balls, not tubes. And because the researchers are trying to study the vaginal lining, which isn\u2019t spherical, they break up the organoids to make \u201copen-faced tissue layers\u201d, says Patras. On one side, the cells have media that nourishes them. On the other, \u201cthey\u2019re seeing air, which is what they would see in the human tissue,\u201d she says.<\/p>\n
One of the team\u2019s goals is to look at whether beneficial microorganisms that are found typically in the vagina, such as Lactobacillus, can protect the vaginal tract from being colonized by harmful microbes. Although the assumption has long been that the pathogens that cause urinary tract infections come from the gut, some research suggests that the vaginal microbiome could play a part. Preventing colonization there might reduce the risk of infections in the urinary tract.<\/p>\n
Ovaries are also getting the organoid treatment, both for studying fertility and the transition to menopause, which comes with a host of aggravating symptoms and an increased risk of heart disease, stroke and osteoporosis.<\/p>\n
Francesca Duncan, a reproductive biologist at Northwestern University\u2019s Feinberg School of Medicine in Chicago, Illinois, and her colleagues are using ovarian organoids to study reproductive ageing. Researchers in this field have focused conventionally on the ovary\u2019s follicle. \u201cThat\u2019s the kind of functional unit,\u201d says Duncan. It\u2019s the part that generates hormones and contains the developing egg. About a decade ago, however, researchers in her lab discovered that, in mice, it\u2019s not just the egg that ages \u2014 the ovary becomes inflamed and stiffer with age. She suspects that this ovarian ageing could influence both the number and quality of the eggs and, therefore, affect fertility.<\/p>\n
Duncan wanted an in vitro model to study this ageing process and whether drugs might be able to reverse it. Plenty of labs have managed to grow follicles outside the ovary. They\u2019ve even managed to get those follicles to give rise to eggs. But Duncan wanted to study the other cells that make up the ovary. When a graduate student suggested trying to grow an ovarian organoid, Duncan was sceptical. \u201cIt seemed like a fad,\u201d she says. But the student was so enthusiastic that Duncan gave the project the green light. The research has already been \u201creally, really fruitful\u201d, she says.<\/p>\n
So far, Duncan\u2019s team has created ovarian organoids from the ovaries of mice and rhesus macaques, finding, for example, that the stiffening of individual cells in the ovary might be responsible for how the ovary tissue stiffens as it ages.<\/p>\n
The team\u2019s next step is to develop human ovarian organoids to screen compounds that could stave off this stiffening or even reverse it, Duncan says.<\/p>\n
Researchers are also using organoids to study ovarian cancer, the fifth-leading cause of cancer-related deaths in women. Some teams are studying how the disease emerges by examining organoids that mimic the fallopian tube. That\u2019s because research suggests that the vast majority of the deadliest ovarian cancers actually originate there. Other groups are modelling ovarian and other cancers of the female reproductive tract by growing organoids from tumour tissue that has been taken from people with the disease.<\/p>\n
Although researchers are learning a great deal from organoids that represent a single tissue or cell type, some teams are hoping to learn even more by combining them with other organoids or incorporating them into more-complex systems. Endometrial organoids can be combined with placental organoids to study a fuller picture of invasion, for example. Or they can be mixed with lab-created embryo models to study implantation.<\/p>\n
Even these more-intricate organoids won\u2019t capture the full complexity of human tissue. But they don\u2019t have to. Organoids might be a reductionist model, but \u201cstill they\u2019re revealing so much,\u201d Turco says. \u201cI keep getting surprised.\u201d<\/p>\n
This article is reproduced with permission and was first published on September 23, 2025.<\/p>\n","protected":false},"excerpt":{"rendered":"
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