Scientists led by Julie Kim, PhD, the Susy Y. Hung Research Professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine, have developed a novel stem cell platform that provides a new way to study the biology of endometriosis in humans more accurately than current model systems.
As detailed in a recent study published in Science Advances, the new platform, which uses induced pluripotent stem cells derived from patients with endometriosis, can capture key molecular and hormonal features of the disease in a controlled human context, providing a foundation for future research about the disease aimed at defining disease-specific mechanisms.
“Endometriosis is a debilitating disease that doesn’t get enough attention because it doesn’t put a woman’s life in jeopardy; it just causes extreme morbidity. It needs more attention, we need more research, and we need to fine tune the way we treat women with endometriosis and test novel therapies,” Kim said. “This platform is a significant advancement, and I think others can do a lot with this in future research.”
Endometriosis is a chronic disease in which tissue that is similar to the inner lining of the uterus grows outside of the uterus, affecting the ovaries, fallopian tubes and other pelvic organs. According to the World Health Organization, endometriosis affects an estimated 10 percent of reproductive age women worldwide.
While endometriotic lesions act like the lining inside the uterus — it thickens, breaks down and bleeds with each menstrual cycle — the tissue doesn’t leave the body. This contributes to increased pelvic pain, heavy bleeding during menstrual cycles and an increased risk of infertility.
Medications are commonly prescribed to help manage pain and symptoms, and surgery may be considered to remove any lesions, adhesions, scar tissue or, in some cases, the uterus entirely. However, there is currently no cure.
Mechanistic and translational studies about endometriosis, which have aimed to utilize human endometrial stromal (connective tissue) cells, have also been constrained due to limited tissue availability, variability in donor cycle stage and the lifespan of stromal cells, until now.
In response, the scientists developed a novel platform that uses induced pluripotent stem cells (iPSCs) derived from patients with endometriosis that accurately model stromal cell differentiation and hormone responsiveness in humans.
A unique feature of iPSCs is that they retain the patient’s genetic background, allowing scientists to model disease using cells that carry the inherited genetic risk factors associated with endometriosis. This is particularly important because endometriosis has a well-established heritable component, Kim said.
“It’s unclear the exact details about the genetics of endometriosis in terms of the development and progression of the disease, but this new model system allows us to study an individual’s genetic background in a way that was not previously possible,” Kim said. “We can make cell types that are involved in the disease and to follow how they develop, behave and interact with other cells. In other words, we can recreate key aspects of endometriotic tissues outside the body.”
To validate their platform, the scientists compared gene expression in their iPSC-derived endometrial stromal fibroblasts from patients with endometriosis to previously published gene expression analyses of adult endometrial stromal cells from endometriosis.
From this analysis, they observed a significant number of similar pathways associated with endometriosis. Interestingly, the iPSC-derived cells showed a distinct difference in the epigenetic pathways compared to adult cells from endometriosis.
“Because epigenetic changes are influenced by environmental cues such as chronic inflammation, our observations suggest that endometriosis is characterized not only of genetic susceptibility but also of persistent inflammatory signals that reprogram how genes are regulated,” Kim said.
Moving forward, Kim said her team is now using the iPSCs to develop macrophages (specialized white blood cells) to study whether macrophages promote increased inflammation in endometriosis and fail to clear diseased tissues. Thy are also differentiating iPSCs to nociceptor sensory neurons to better understand why patients with endometriosis experience increased pain.
“These are all questions that current models cannot fully answer, but now we have a system where we can manipulate different factors and study them in a controlled environment, giving us an unprecedented opportunity to understand how endometriosis develops and progresses. It’s an exciting step forward for the field,” Kim said.
Hannah McDowell, a graduate student in the Driskill Graduate Program in Life Sciences (DGP), was lead author of the study.
Co-authors include Shiyang Sun, PhD, and Ross McNally, PhD, postdoctoral fellows in the Kim laboratory; K. Grace Foley, PhD, a former student in the Driskill Graduate Program in Life Sciences (DGP); Angel Alvarez, PhD, research assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Neuromuscular Disease and director of the Stem Cell Core; Christina Boots, MD, ‘18 MSCI, associate professor of Obstetrics and Gynecology in the Division of Reproductive Endo and Infertility; Magdy Milad, MD, MS, the Albert B. Gerbie, MD, Professor of Obstetrics and Gynecology; and Cassandra Huerta, MS, a former graduate student in the Master of Science in Reproductive Science and Medicine program and a senior research technologist at the Ann & Robert H. Lurie Children’s Hospital of Chicago.
This work was supported by the Friends of Prentice, the Endometriosis Foundation, the Eunice Kennedy Shriver National institute of Child Health and Human Development grant R01HD114195 and T32 training grant HD094699, National Institute of Environmental Health Sciences grant UH3 ES029073, and National Cancer Institute NIH T32 training grant CA009560.
