Transforming growth factor beta1 from endometriomas promotes fibrosis in surrounding ovarian tissues via Smad2/3 signaling.

To elucidate whether the endometriotic cells of endometriomas synthesize transforming growth factor beta1 (TGF-beta1) and understand how it affects surrounding ovarian tissue. We collected biopsies of the cystic walls from 42 endometriomas and 29 mature teratomas and compared mRNA and protein expression of fibrosis-related factors between the cystic walls. Then we detected TGFB1 mRNA synthesis in endometriomas, and tested TGF-beta1 fibrotic effect in vitro. Moreover, we verified the expression of Smad2/3 signaling components in the endometriotic cystic wall in order to understand whether TGF-beta1/Smad signaling is involved in fibrosis formation of the tissue surrounding endometriomas. The cystic walls from endometriomas demonstrated severe adhesion to ovarian tissue and obvious fibrosis compared with the mature teratomas, which was proven by the increased mRNA expression of fibrotic markers. Additionally, TGFB1 was obviously expressed in the endometriotic cystic wall, and total TGFB1 protein was significantly higher in the cystic walls of endometriomas than mature teratomas. Interestingly, TGFB1 mRNA was confirmed to be specifically synthesized in the endometriotic loci through fluorescence in situ hybridization. Cultured endometriomas derived stromal cells showed obvious fibrosis after exposed to TGF-beta1. Furthermore, components of the TGF-beta1/Smad pathway such as Smad2, Smad3, Smad4, and their phosphorylated forms were also expressed in the same location as TGF-beta1, TGF-beta receptor1, and fibrotic factors expressed in the endometriotic cystic walls. In summary, endometriotic cells of endometriomas synthesize TGF-beta1 leading to fibrosis and adhesion to ovarian tissues, and TGF-beta1/Smad signaling pathway is involved in this pathological process.

Ovarian Fibrosis: A Phenomenon of Concern.

OBJECTIVE: Ovarian fibrosis is characterized by excessive proliferation of ovarian fibroblasts and deposition of extracellular matrix (ECM) and it is one of the principal reasons for ovarian dysfunction. This review aimed to investigate the pathogenetic mechanism of ovarian fibrosis and to clarify the relationship between ovarian diseases and fibrosis. DATA SOURCES: We searched PubMed for English language articles published up to November 2016. The search terms included ovarian fibrosis OR fibrosis, ovarian chocolate cyst OR ovarian endometrioma, polycystic ovarian syndrome (PCOS), premature ovarian failure, ECM, matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), transforming growth factor-beta 1 (TGF-ß1), connective tissue growth factor (CTGF), peroxisome proliferator-activated receptor gamma (PPAR-γ), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and combinations of these terms. STUDY SELECTION: Articles were obtained and reviewed to analyze the pathogenic mechanism of ovarian fibrosis and related ovarian diseases. RESULTS: Many cytokines, such as MMPs, TIMPs, TGF-ß1, CTGF, PPAR-γ, VEGF, and ET-1, are involved in ovarian fibrogenesis. Ovarian fibrogenesis is associated with various ovarian diseases, including ovarian chocolate cyst, PCOS, and premature ovarian failure. One finding of particular interest is that fibrogenesis in peripheral tissues around an ovarian chocolate cyst commonly causes ovarian function diminution, and therefore, this medical problem should arouse widespread concern in clinicians worldwide. CONCLUSIONS: Patients with ovarian fibrosis are susceptible to infertility and tend to have decreased responses to assisted fertility treatment. Thus, protection of ovarian function should be a priority for women who wish to reproduce when making therapeutic decisions about ovarian fibrosis-related diseases.

Tissue engineered bulking agent with adipose-derived stem cells and silk fibroin microspheres for the treatment of intrinsic urethral sphincter deficiency.

In this study we developed a tissue engineered bulking agent that consisted of adipose-derived stem cells (ADSCs) and silk fibroin microspheres to treat stress urinary incontinence caused by severe intrinsic sphincter deficiency (ISD). ISD models were established by completely transection of the bilateral pudendal nerve (PNT) and confirmed by the decreased leak-point pressure (LPP) and increased lumen area of urethra. Injection of silk fibroin microspheres could recover LPP and lumen area at 4 weeks but its efficacy disappears at 8, 12 weeks. Moreover, it was exciting to find that tissue engineered bulking agent brought long-term efficacy (at 4, 8, 12 weeks post-injection) on the recovery of LPP and lumen area. Concomitantly with the function, tissue engineered bulking agent treated group also improved the urethral sphincter structure as exhibited by better tissue regeneration. The findings showed that silk fibroin microspheres alone could work effectively in short-term, while tissue engineered bulking agent that combined silk fibroin microspheres with ADSCs exhibited promising long-term efficacy. This study developed a new strategy of tissue engineered bulking agent for future ISD therapy.