Endometriosis lesion development hinges critically on the interaction between transplanted endometrial tissue, the peritoneal cavity, and the immune system. TGFβ1 is a pleiotropic growth factor that lies at the core of a network of differentially-regulated genes in endometriotic lesions, suggesting that it may be key to disease pathogenesis. Although we know that TGFβ1 deficiency in mice results in smaller endometriosis-like lesions, a detailed molecular and cellular understanding of TGFβ1’s role in endometriosis is lacking.
In macrophages, TGFβ1 skews phenotype towards “wound-healing” (M2) in preference to “pro-inflammatory” (M1). A predominance of M2 macrophages over M1 is likely to be important in the formation and persistence of endometriotic lesions, and this switch is associated with a characteristic microRNA expression profile. Our studies suggest that M2 macrophage microRNAs are overexpressed in endometriotic lesions, co-localise with macrophages in humans, and temporally correlate with the appearance of M2 macrophages in mouse endometriosis-like lesions.
An abundant source of TGFβ1 is seminal plasma, the acellular fraction of semen which contacts female reproductive tract tissues post-coitus and induces cytokine production therein. We hypothesised that SP might promote endometriosis via similar mechanisms, and treated human endometrial tissue with SP prior to xenotransplantation in immunocompromised mice to test this. The findings indicated that SP treatment results in larger endometriosis-like lesions with increased epithelial cell proliferation, and causes dramatic changes in endometrial cytokine profiles.
Finally, array studies indicate that tissue remodelling in endometriotic lesions involves osteogenic factors. Our data demonstrate a direct effect of TGFβ1 to induce osteoblast-specific transcription factors in primary human endometrial stromal cells. This effect may underlie histopathologic findings of dystrophic calcification including psammoma bodies in endometriotic lesions.
In summary, the increasing evidence that TGFβ1 drives several key pathological processes in endometriosis lesions suggests that it might be a potential therapeutic target in endometriosis.