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Researchers identify source of inflammatory cells in endometriosis

NIH-funded study uses lab cultures to trace problem cells back to their source

Thursday, April 21, 2016

Researchers have discovered the source of a cell type central to endometriosis, an oftentimes painful disease that occurs when tissue that lines the inside of the uterus grows outside of the uterus. The NICHD-funded study, which appears in the May 2016 issue of Biology of Reproduction, contributes to the understanding of endometriosis and may one day contribute to treatments for the condition.

Background

The endometrium provides an environment for an embryo to implant and grow within the uterus. This unique tissue depends on signals from hormones, such as estrogen and progesterone, to develop and function. In the absence of a pregnancy, the endometrium is shed during menstruation and later re-formed. However, during pregnancy, progesterone signals cells called endometrial stromal fibroblasts (eSF) to perform a number of tasks, such as helping to create a blood supply for the embryo.

In endometriosis, eSF are unable to respond to progesterone and do not function properly, which can lead to infertility or poor pregnancy outcomes, such as problems with the placenta, miscarriage, and preterm birth. The disease also produces inflammation and pain. To understand the cause of endometriosis, the researchers sought to identify how eSF develop and, in endometriosis, how they become prone to inflammation.

Results

Led by Linda C. Giudice, M.D., from the University of California, San Francisco, the researchers developed an experimental model using tissue samples collected from women with and without endometriosis. The team confirmed that maintaining these samples over time in the laboratory did not change the cells’ behavior or shape, suggesting that this system models endometriosis accurately.

In the study, the team found that eSF can develop from mesenchymal stem cells (eMSC), which promote tissue repair and regeneration after menstruation. Next, the researchers studied eSF grown from eMSC, comparing samples from endometriosis patients and from women without the disease. The researchers discovered that in endometriosis, eSF lose the ability to respond to progesterone during the eMSC stage of their development, indicating that this defect occurs before the cells become fibroblasts. In contrast, the inflammatory behavior occurs later, suggesting that fibroblasts develop this trait while in the endometrium.

Significance

“The exact causes of endometriosis are not yet fully known, and this hinders the ability of health care professionals to cure the disease or prevent complications like infertility,” said Louis DePaolo, Ph.D., chief of NICHD’s Fertility and Infertility Branch. “Identifying the origin of abnormal endometrial cells and learning how they respond to progesterone may help in identifying promising targets for future therapies.”

Next Steps

More work is needed to build upon the results of this study, which is supported by NICHD’s National Centers for Translational Research in Reproduction and Infertility. Researchers will need to identify what parts of the endometrium cause eSF to develop inflammatory properties in endometriosis. They also need to understand how eMSC lose their ability to respond to progesterone.

Reference

Barragan F, Irwin JC, Balayan S, Erikson DW, Chen JC, Houshdaran S, Piltonen TT, Spitzer TLB, George A, Rabban JT, Nezhat C, and Giudice LC. Endometrial Fibroblasts Derived from Mesenchymal Progenitors Inherit Progesterone Resistance and Acquire an Inflammatory Phenotype in the Endometrial Niche in Endometriosis. Biology of Reproduction DOI: 10.1095/biolreprod.115.136010(2016)

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