Scientists have created organoids capable of regenerating similarly to the endometrium, the uterine lining that sheds and reconstructs during the menstrual cycle. These miniature 3D structures were used to mimic rarely observed repair mechanisms, potentially leading to new therapeutic approaches for tissue regeneration and wound healing. The study was published in Cell Stem Cell on April 28.
The endometrium uniquely heals after menstrual shedding without forming scars, yet the process remains largely unexplained. Prior to this research, replicating this activity in a lab environment was challenging, and studying it directly in humans was deemed too invasive, according to co-author Konstantina Nikolakopoulou, a molecular biologist who conducted the research at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.
“Having a model system for experimentation is remarkable,” says Deena Emera, an evolutionary biologist at the Buck Institute for Research on Aging in Novato, California. Understanding endometrial repair could enhance knowledge of gynecological conditions like endometriosis and may also be applicable to regeneration research in other types of tissue.
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Lab-grown Tissue
Nikolakopoulou’s organoids were based on models developed by her former supervisor in 2017. These models involved taking a biopsy from a person’s endometrium, isolating the cell types, and combining only the epithelial cells—the primary tissue type in the endometrium—with a gelatinous membrane. This allowed the cells to self-organize into a hollow, spherical form resembling the endometrium.
Nikolakopoulou and her team advanced this model by replicating the menstrual cycle in the organoids. Initially, they exposed the organoids to estrogen and progesterone, hormones that regulate menstrual phases. The hormones were then withdrawn, mimicking the natural reduction that triggers endometrial shedding in humans. Lacking the cell types that initiate shedding, the team used a pipette to mechanically degrade the tissue, observing its regeneration akin to the human endometrium.
Nikolakopoulou notes that these organoids are simplified, containing only epithelial cells and not the full array of cell types like immune, stromal, and endothelial cells, or components such as oxygen and blood. She suggests it is important to first “break down the puzzle, and then start increasing complexity.”
Luminal Helpers
Earlier studies in primates indicated that deep-tissue stem cells are key to endometrial renewal.
However, Nikolakopoulou and her team discovered that luminal cells, another type of epithelial cell located on the endometrium’s surface, played a role in the tissue released by the organoids. These cells assist embryo implantation in the endometrium before pregnancy.
The researchers also found that luminal cells expressed a gene called WNT7A, known to aid tissue regeneration in primates.
Intrigued by WNT7A, they cloned the organoids and used gene editing to eliminate it, discovering that the clones had reduced growth and survival compared to the original organoids.
Examining some endometrial samples from humans, they also identified luminal cells and WNT7A expression before the endometrium reformed, confirming their role in regeneration.
For future organoid development, Nikolakopoulou suggests increasing complexity to better represent the uterine microenvironment. Emera concurs, noting that more advanced organoid models with diverse cell types could more accurately replicate the tissue breakdown process than the current mechanical method.
This article is reproduced with permission and was first published on May 1, 2026.
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