Researchers have developed organoids capable of regenerating like the endometrium, the lining of the uterus which sheds and reforms during the menstrual cycle. The team used the miniature 3D structures to simulate rarely observed repair processes, which could inform future therapeutic strategies for tissue renewal and wound healing. The results were published in Stem cell on April 28.
The endometrium has a unique ability to repair itself after menstrual discharge without leaving scars, but how it does this remains a mystery. Until this study, it was difficult to reproduce the activity in the laboratory and studying it in humans is too invasive, says co-author Konstantina Nikolakopoulou, a molecular biologist who led the research at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
“It’s fantastic to have a model system that you can experiment on,” says Deena Emera, an evolutionary biologist at the Buck Institute for Research on Aging in Novato, California. Knowledge about endometrial repair will not only help scientists improve the understanding of gynecological diseases such as endometriosis, but could also be relevant to research into the regeneration of other tissues.
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Lab-grown tissue
Nikolakopoulou’s organoids were developed based on models created by his former supervisor in 2017. For these models, researchers took a biopsy of a person’s endometrium, separated the cell types, and mixed only the epithelial cells — the main type of tissue in the endometrium — with a gelatinous membrane. This allowed the cells to self-organize into a hollow, spherical structure that acted like the endometrium.
Nikolakopoulou and his team took the model to the next level by mimicking the menstrual cycle in its cells. First, they treated the organoids with estrogen and progesterone, hormones that signal the transition of menstrual phases. The team then removed the hormones, which happens naturally at this point in the cycle due to the activity of the ovaries. In men, reduced progesterone causes endometrial shedding, or menstruation. The type of cells that trigger shedding were not present in the organoid, meaning the team had to mechanically break down the tissue using a pipette to simulate degeneration. They then observed it regenerate, as in a human endometrium.
Nikolakopoulou says organoids are simple and contain only epithelial cells rather than a complete microenvironment of various cell types, such as immune, stromal and endothelial cells, and components such as oxygen and blood. It’s best to start by understanding how to “break down the puzzle, and then start increasing the complexity,” she says.
Luminal aids
Previous research in primates has suggested that deep tissue stem cells are responsible for endometrial turnover.
But when Nikolakopoulou and his colleagues analyzed the tissue released by the organoids, they found that luminal cells, another type of epithelial cell, were involved. Located on the surface of the endometrium, these cells help embryos implant in the endometrium before pregnancy.
The team also discovered that luminal cells expressed a gene called WNT7Aknown to promote tissue regeneration in primates.
Intrigued by the presence of WNT7Aresearchers cloned the organoids and used gene editing to remove them. They found that the growth and survival potential of the clones was compromised compared to the original organoids.
When they examined some of the rare endometrial samples they had, they also detected the presence of luminal cells and expression of WNT7A before endometrial reformations, confirming their role in regeneration.
Future directions for organoid development should involve increasing the complexity represented in the uterine microenvironment, says Nikolakopoulou. Emera agrees that more advanced organoid models with a greater diversity of cell types could mimic the process of tissue degradation more accurately than the team’s mechanical method.
This article is reproduced with permission and has been published for the first time May 1, 2026.
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