REGULATION OF MICRORNA-21 AND ITS ROLE IN FIBROSIS IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS

Endometriosis is one of the most common causes of chronic pelvic pain and infertility that affects 10% of women of reproductive age. A delay of up to 9 years is estimated between the onset of symptoms and the diagnosis of endometriosis. Endometriosis is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites, however, advances in the research of endometriosis has some authors believing that endometriosis should be re-defined as “a fibrotic condition in which endometrial stroma and epithelium can be identified.” There are several theories on the etiology of the disease, but the origin of endometriosis remains unclear. MicroRNAs (miRNAs) are naturally occurring posttranscriptional regulatory molecules that potentially play a role in endometriotic lesion development. The presence of endometriotic lesions can alter miRNAs expression in both the eutopic endometrium and ectopic lesions. There is evidence that suggests that miRNAs, including miR-21, participate in the fibrotic process in different organs including the heart, kidney, liver and lungs. This dissertation has aimed to understand the role of miR-21, which is upregulated in endometriosis, and the mechanisms that can contribute to the development of fibrosis and lesion development in endometriosis. The studies have been focused on the mechanisms by which IL-6 regulates miR-21 and how this miRNA contributes to TGF-β signaling pathway by blocking Smad7, promoting fibrosis and lesion development. These studies collectively showed that inflammation and fibrosis are present at a very early stage of endometriosis. The inflammatory environment in the peritoneal cavity of women with endometriosis, which includes the cytokine IL-6, can regulate the expression of miR-21 in vitro and in vivo. The upregulation of miR-21 was correlated with the development of fibrosis during lesion progression of endometriosis, but other components may be also implicated during this process that may contribute to the development of fibrosis. These studies also revealed that B cells could play an important role, however their function remains unknown and should be further investigated in the future. Future work should aim to understand the mechanisms that drive miR-21 to regulate fibrosis in endometriosis and the potential therapeutic mechanisms to treat the disease. In addition to this, further studies should also be focused on the role of B cells that would help to explain their function during the development of endometriosis and could potentially serve as suitable candidates for new therapeutic strategies. This could open up different and less invasive approaches for the treatment of women with endometriosis.