The untapped potential of menstrual blood stem cells

About 20 years ago, a biologist named Caroline Gargett looked for extraordinary cells in tissue removed during a hysterectomy. The cells came from the endometrium, which lines the inside of the uterus. When Gargett grew 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 rounded and the other elongated and conical, with whisker-like protuberances.

Gargett had strong suspicions that these were adult stem cells, rare, self-renewing cells, some of which can give rise to many different types of tissues. She and other researchers had long believed that the endometrium contained stem cells, given its remarkable ability to regenerate each month. This tissue, which serves as an implantation site for the embryo during pregnancy and is shed during menstruation, sheds and grows back about 400 times before the woman reaches menopause. But although scientists had isolated adult stem cells from many other regenerating tissues—such as bone marrow, heart, and muscle—“no one had identified adult stem cells in the endometrium,” Gargett says.

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These cells are highly prized for their potential to repair damaged tissues and treat diseases such as cancer or heart failure. However, their number is low throughout the body and obtaining them can be complicated, since it requires a surgical biopsy or the extraction of bone marrow with a needle. The possibility of a previously untapped source of adult stem cells was exciting in itself, Gargett says. And she also raised the interesting possibility of a new approach to historically neglected female diseases, such as endometriosis.

Before they could say that the cells were actually stem cells, Gargett and his team at Monash University in Australia had to put them through a series of rigorous tests. First, they measured the cells' ability to proliferate and self-renew, and found that some of them could divide into about 100 cells in a week. They also showed that the cells could differentiate into endometrial tissue and identified certain telltale proteins present in other types of stem cells.

Gargett, now also at the Hudson Institute of Medical Research in Australia, and his colleagues characterized several types of self-renewing cells in the endometrium. But only the whiskered cells, called endometrial stromal mesenchymal stem cells, were truly “multipotent,” with the capacity to become fat cells, bone cells, or even the smooth muscle cells of organs such as the heart.

Stem cells from the endometrium can be obtained through a biopsy or in menstrual blood.Knowable

Around the same time, two independent research teams made another surprising discovery: some mesenchymal stem cells from the endometrial stroma could be found in menstrual blood. Gargett was surprised that the body shed its precious stem cells so easily. Since they are so important for survival and organ function, he did not believe that the body would “waste” them by getting rid of them. But he quickly realized the importance of the finding: instead of resorting to an invasive surgical biopsy to obtain the elusive stem cells he had identified in the endometrium, he could collect them through the menstrual cup.

Since then, more detailed studies of the endometrium have helped explain how a subset of these precious endometrial stem cells—called menstrual stem cells—end up in menstrual blood. The endometrium has a deeper basal layer that remains intact and an upper functional layer that is shed during menstruation. During a menstrual cycle, the endometrium thickens and prepares to nourish the fertilized egg, and then shrinks as the top layer is shed.

Gargett's team has shown that these special stem cells are present in both the lower and upper layers of the endometrium. The cells typically surround 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 each month during menstruation. This layer is crucial for pregnancy, as it provides support and nourishment to the developing embryo. The lining, and the endometrial stem cells that stimulate its growth, also appear to play an important role in infertility: an embryo cannot implant if the lining does not thicken enough.

Endometrial stem cells have also been linked to endometriosis, a painful disease that affects around 190 million women and girls worldwide. Although not all the details of this disease are known, the researchers' hypothesis is that one of the factors that contributes to it is the reflux of menstrual blood into the fallopian tubes, the tubes that transport the egg from the ovaries to the uterus. This reflux carries blood into the pelvic cavity, a funnel-shaped space between the bones of the pelvis. Endometrial stem cells that settle 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 continue to develop a reliable, non-invasive test to diagnose endometriosis, and patients wait on average almost seven years before receiving a diagnosis. But studies have shown that stem cells taken from the menstrual blood of women with endometriosis have different shapes and gene expression patterns than cells from healthy women. Several laboratories are working on using these differences in menstrual stem cells to identify women at higher risk of suffering from the disease, which could speed up diagnosis and treatment. Menstrual stem cells may also have therapeutic applications. Some researchers working with mice, for example, have found that injecting menstrual stem cells into the blood of rodents can repair damaged endometrium and improve fertility.

Other research in laboratory animals suggests that menstrual stem cells could have therapeutic potential beyond gynecological diseases. In a couple of studies, for example, 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 heal wounds in mice.

Stem cells are differentiated by their capabilities.Knowable

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 trying to develop human therapies. She and her colleagues are using endometrial stem cells—those taken directly from endometrial tissue, rather than menstrual blood—to design a mesh to treat pelvic organ prolapse, a common and painful condition in which the bladder, rectum, and or the uterus are pushed into the vagina due to weak or injured muscles.

This condition is usually caused by childbirth. Existing treatments use synthetic mesh to reinforce and support weak pelvic tissues. But adverse immune reactions to these materials have forced these meshes to be removed from the market. Gargett's research—so far conducted only in animal models—suggests that using the patient's own endometrial stem cells to coat biodegradable meshes could give better results.

Despite the relative convenience of harvesting multipotent adult stem cells from menstrual blood, research exploring and harnessing the power of stem cells—and their potential role in disease—still represents a small fraction of stem cell research, says Daniela Tonelli Manica, an anthropologist at the State University of Campinas in Brazil. In 2020, menstrual stem cell research accounted for only 0.25% of all mesenchymal cell research, while bone marrow stem cells accounted for 47.7%.

Manica attributes the slow adoption of menstrual stem cells in part to misogynistic ideas that uteruses are outside the norm, and reactions of disgust. “There's definitely something 'nasty' about menstrual blood,” says Victoria Male, a reproductive immunologist at Imperial College London and co-author of a paper on uterine immune cells.

in the

2023

Annual Review of Immunology .

Cultural taboos surrounding menstruation—and a general lack of investment in women's health research—can make it difficult to obtain funding, Gargett says. Immunologist Male has faced similar challenges: It was easier to get funding when she was studying immune cells in liver transplantation than it is now when she works with immune cells in the uterus, she says.

“If we want more research on menstrual fluids, we need more funding,” says Male, noting that the logistics of collecting menstrual fluids over several days can be expensive. For that to happen, “we have to address sex and gender bias in research funding.” With more equitable investments, she and others hope that menstruation will be recognized as an exciting new frontier in regenerative medicine—and not just a monthly inconvenience.

Sneha Khedkar

is a biologist and freelance science journalist in Bengaluru, India. Her work has appeared in Undark, The Xylom, and Live Science, among other outlets.

Article translated by

Debbie Ponchner

.

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