Stem cells in menstrual blood could revolutionize medicine

About 20 years ago, a biologist named Caroline Gargett began researching some remarkable cells in tissue taken during hysterectomy surgeries. The cells came from the endometrium, which lines the inside of the uterus. When Gargett cultured the cells in a petri dish, they looked like round clumps surrounded by a clear, pink medium. But when she examined them under a microscope, she saw what she was looking for: two types of cells, one flat and round, the other long and pointed with whisker-like protrusions.

According to a report by Knowable Magazine, Gargett strongly suspected that the cells were adult stem cells—that is, rare, self-renewing cells, some of which can give rise to many different tissue types. She and other researchers had long assumed that the endometrium contained stem cells, given its remarkable capacity to regrow itself every month. The tissue, which provides a place for the embryo to implant during pregnancy and is shed during menstruation, goes through about 400 cycles of shedding and regrowth before a woman reaches menopause. Gargett says that although scientists have isolated adult stem cells from many other regenerating tissues, including bone marrow, heart, and muscle, "no one had identified adult stem cells in the endometrium."

Such cells are highly valuable due to their potential to repair damaged tissue and treat diseases like cancer and heart failure. However, they are found in small numbers in the body and can be difficult to obtain, requiring surgical biopsy or the extraction of bone marrow with a needle. Gargett says the prospect of finding a previously untapped source of adult stem cells is exciting in itself. It also raised the exciting possibility of a new approach to long-neglected women's health issues such as endometriosis.

Gargett and her team at Monash University in Australia had to put the cells through a series of rigorous tests before claiming they were indeed stem cells. First, they measured the cells' ability to proliferate and self-renew, finding that some could divide into about 100 cells within a week. They also showed that the cells could indeed differentiate into endometrial tissue and identified specific proteins found in other types of stem cells.

Gargett and her colleagues, who now also work at Australia's Hudson Institute of Medical Research, continued to characterize the various types of self-renewing cells in the endometrium. However, only the whisker-like cells, called endometrial stromal mesenchymal stem cells, were truly "multipotent," with the ability to turn into fat cells, bone cells, and even smooth muscle cells found in organs like the heart.

Around the same time, two independent research teams made another surprising discovery: some endometrial stromal mesenchymal stem cells can be found in menstrual blood. Gargett was surprised that the body could shed its valuable stem cells so easily. She did not think the body would "waste" them by discarding them, as they are crucial for the survival and function of organs. But she immediately realized the significance of the finding: instead of relying on an invasive surgical biopsy to obtain the hard-to-find stem cells she had detected in the endometrium, she could collect them via a menstrual cup.

Since then, more detailed studies on the endometrium have helped explain how a subset of these valuable endometrial stem cells (called menstrual stem cells) mix into menstrual blood. The endometrium has a deeper basal layer that remains intact and an upper functional layer that is shed during menstruation. During a single menstrual cycle, the endometrium thickens as it prepares to nourish a fertilized egg, then shrinks as the top layer is shed.

Gargett's team showed that these specific stem cells are found in both the lower and upper layers of the endometrium. The cells typically wrap around blood vessels in a crescent shape, where they are thought to help stimulate vessel formation and play a vital role in repairing and regenerating the top layer of tissue that is shed every month during menstruation. This layer is crucial for pregnancy and provides support and nourishment to the developing embryo. The layer and the endometrial stem cells that enable its growth also appear to play an important role in infertility: if the layer does not thicken sufficiently, the embryo cannot implant.

Endometrial stem cells have also been linked to endometriosis, a painful condition that affects approximately 190 million women and girls worldwide. Although much about this condition is not fully understood, researchers suggest that the backflow of menstrual blood into a woman's fallopian tubes—the channels that carry the egg from the ovaries to the uterus—is a contributing factor. This retrograde flow carries blood into the pelvic cavity, a funnel-shaped space between the bones of the pelvis. Endometrial stem cells that accumulate in these areas can cause endometrial-like tissue to grow outside the uterus, leading to lesions that can cause excruciating pain, scarring, and in many cases, infertility.

Researchers are still developing a reliable, non-invasive test to diagnose endometriosis, and patients wait an average of about seven years before receiving a diagnosis. However, studies have shown that stem cells collected from the menstrual blood of women with endometriosis have different shapes and gene expression patterns than cells taken from healthy women. Some laboratories are working on ways to use these differences in menstrual stem cells to identify women at higher risk for the condition, leading to faster diagnosis and treatment. Menstrual stem cells may also have therapeutic applications. For example, some researchers working on mice have found that injecting menstrual stem cells into the rodents' blood can repair damaged endometrium and improve fertility.

Other research on laboratory animals suggests that menstrual stem cells may have therapeutic potential beyond gynecological diseases. For example, in several studies, injecting menstrual stem cells into diabetic mice stimulated the regeneration of insulin-producing cells and improved blood sugar levels. In another, treating injuries with stem cells or their secretions helped wounds heal in mice.

A handful of small but promising clinical trials have found that menstrual stem cells can be transplanted into humans without adverse side effects. Gargett's team is also working on developing human therapies. She and her colleagues are using endometrial stem cells (taken directly from endometrial tissue rather than menstrual blood) to create a mesh to treat pelvic organ prolapse, a common and painful condition where the bladder, rectum, or uterus slips toward the vagina, to support weak or injured muscles.

This condition is often caused by childbirth. Current treatments use synthetic meshes to strengthen and support weak pelvic tissues. However, adverse immune reactions to these materials have led to these meshes being withdrawn from the market. Gargett's research, which has so far only been conducted in animal models, suggests that using the patient's own endometrial stem cells to coat biodegradable meshes could yield better results.

Anthropologist Daniela Tonelli Manica at the State University of Campinas in Brazil says that despite the relative ease of collecting adult multipotent stem cells from menstrual blood, research investigating and utilizing the power of stem cells (and their potential role in disease) still represents a small fraction of stem cell research. As of 2020, she found that menstrual stem cell research accounted for only 0.25 percent of all mesenchymal cell research, while bone marrow stem cells represented 47.7 percent.

Manica attributes the slow adoption of menstrual stem cells partly to misogynistic ideas that wombs are outside the norm and to reactions of disgust. Victoria Male, a reproductive immunologist at Imperial College London and co-author of a 2023 paper on uterine immune cells in the Annual Review of Immunology, agrees, saying, "There is definitely a 'yuck factor' associated with menstrual blood."

Gargett says that cultural taboos surrounding menstruation and the general lack of investment in women's health research can make securing funding difficult. Immunologist Male has faced similar challenges, saying that finding funding while working on immune cells in liver transplants was easier than it is now that she works on immune cells in the uterus.

"If we want more research on menstrual fluid, we need more funding," says Male, noting that the logistics of collecting menstrual fluid over multiple days can be expensive. For this to happen, "we must combat gender and sex bias in research funding." She and others hope that with more equitable investment, menstruation will be recognized not just as a monthly inconvenience, but as an exciting new frontier in regenerative medicine.