Stem Cell Trafficking During Endometriosis: May Epigenetics Play a Pivotal Role?

We read with great interest the paper by Pluchino and Taylor, recently published on your prestigious journal, about the role of stem cell trafficking in the pathogenesis of endometriosis. In particular, we appreciated the clear summary of recent evidence: on one hand, the retrograde menstruation of stem/progenitor cells from endometrial niches to the peritoneal cavity may underlie the development of endometriosis within the peritoneal cavity; on the other hand, bone marrow-derived stem cells (BMDSCs) may migrate through peripheral circulation, cause endometriosis in remote sites, and also infiltrate eutopic endometrium. These elements open a new scenario that will help to shed light on the pathogenesis of endometriosis and lead us to further comment on them, hoping to trigger a positive debate and address future research directions. Although several theories have been proposed, the pathogenesis of endometriosis still remains controversial: environmental, endocrine, immune, and (epi)genetic factors were all advocated to explain the complex machinery behind the origin and development of endometriotic implants. Some authors hypothesized that endometriosis may be caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis, which differentiates in functional ectopic endometrial tissue within the pelvis after puberty. Conversely, as summarized by Pluchino and Taylor, BMDSCs may be the principal source of extrapelvic endometriosis, as they are able to differentiate directly into endometriosis cells at ectopic locations and are able to migrate and infiltrate eutopic endometrium as was clearly demonstrated in bone marrow transplant recipients. Thus, current data may underlie an apparent dichotomy between 2 different origins of pelvic and extrapelvic implants. Although accurate meta-analysis failed to show robust correlation with gene polymorphisms, genome-wide association studies identified the loci carrying genetic variants, implicated in estrogen-induced cell growth (growth regulation by estrogen in breast cancer 1 [GREB1]), cell adhesion, migration, growth differentiation (vezatin, adherens junctions transmembrane protein [VEZT]; fibronectin 1 [FN1]), inflammation (interleukin 1 alpha [IL1A]), but importantly also in wingless-type mouse mammary tumor virus integration site family (WNT)/ b-catenin signaling. In this regard, epigenetics could be able to explain what genetics is not able to do, since recent evidence suggests that ectopic endometrium has a distinctive epigenetic expression profile. Interestingly, epigenetics changes seem to involve homeobox A (HOXA) clusters and Wnt signaling pathway genes, which are both advocated as possible key determinants of ‘‘embryonic theory’’ of endometriosis. In addition, DNA methylation patterns, histone modifications, and microRNAs (miRNAs) were all found to modulate proliferation, invasiveness, and stemness of endometriotic cells. With respect to the review of Pluchino and Taylor, one could imagine that a dysregulation of miRNAs such as miR-145 may influence the stem cell phenotype via affecting pluripotencyrelated transcription factor expression, whereas a dysregulation of miR-200b may affect developmental plasticity and cell differentiation at ectopic sites by regulating epithelial-tomesenchymal transition and invasive cell growth. Moreover, epigenetics play a major role in modulating the interplay of steroid action and the inflammatory microenvironment, marked as key factors of BMDSC recruitment and differentiation by Pluchino and Taylor. For example, epigenetic regulation of C-X-C chemokine receptor type 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) by estradiol and tamoxifen influences expression of specific DNA methyltransferase splice variants in Ishikawa cells. Moreover, prolonged exposure to a pro-inflammatory environment was shown to influence progesterone receptor B methylation in an endometriotic cell line model, and expression of this receptor is also subject to miRNA regulation. In turn, sex steroids have been shown to be relevant for the mobilization of BMDSCs into the circulation. Based on these elements, we take the opportunity to