Reprogramming a type of patient-derived stem cell to produce healthy uterine cells, called endometrial stromal fibroblasts, may be a potential treatment for endometrial diseases such as endometriosis, a study suggests.
The study, “Generation of Progesterone-Responsive Endometrial Stromal Fibroblasts from Human Induced Pluripotent Stem Cells: Role of the WNT/CTNNB1 Pathway,” was published in the journal Stem Cell Reports.
The defective function of endometrial stromal fibroblasts (EMSF) — a cell type that is important for the cyclic regeneration of the endometrium — plays a key role in the development of endometrial disorders, including endometriosis.
Cell replacement therapies have garnered attention among researchers as a potential therapeutic method to replace cells that are lost or damaged in various diseases.
In particular, researchers at Northwestern Medicine have investigated induced human pluripotent stem cells (iPSCs), which are derived from a patient’s own skin or bone marrow biopsies, and can be differentiated and matured into various cell types. As these cells are obtained from patients, there is no risk of rejection by their immune system.
Hence, EMSF replacement therapy using iPSCs — particularly to restore response to the hormone progesterone (impaired in patients with endometriosis) — can provide a novel approach to treating endometriosis.
“This is huge. We’ve opened the door to treating endometriosis,” Dr. Serdar Bulun, MD, senior author of the study, said in a press release. “These women with endometriosis start suffering from the disease at a very early age, so we end up seeing young high school girls getting addicted to opioids, which totally destroys their academic potential and social lives.”
The uterus differentiates in a number of stages. First, a layer of cells known as the intermediate mesoderm differentiates into the coelomic epithelium (which constitutes the outermost layer of the gonads) followed by the Müllerian duct (which forms the female reproductive tract consisting of various cell types).
Previously, the methodology for differentiating iPSCs to EMSFs was unknown.
In this study, the researchers were able to successfully differentiate human iPSCs into the intermediate mesoderm, coelomic epithelium, Müllerian duct, and finally EMSFs under culture conditions using specific hormonal treatments.
The researchers also found that activation of the WNT/CTNNB1 pathway is critical in the final differentiation step of EMSFs.
Specifically, the WNT/CTNNB1 pathway is a key regulator of progesterone receptor (which mediates the effects of progesterone in the endometrium) expression during differentiation of human iPSCs.
“This finding may be a game changer for novel molecular therapy to improve progesterone resistance seen in a variety of endometrial diseases,” the authors wrote.
This study has shown that cells can be reprogrammed and respond functionally to progesterone, so the next step would be to replace the dysfunctional EMSFs in the uterus with these new and healthy cells, adds Bulun. This means that EMSFs that cause inflammation and pain in the uterus can be replaced with the normally programmed cells. In this way, pain can be eliminated long term.
Additionally, the newly formed and healthy endometrium would be more likely to implant an embryo and help treat infertility, a common condition among women with endometriosis.
“One day we hope to make a whole uterus using this cell-based treatment employing the patient’s own iPS cells,” said Bulun.
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