Mesenchymal Stromal Cells Are More ImmunosuppressiveIn VitroIf They Are Derived from Endometriotic Lesions than from Eutopic Endometrium

Abstract

Endometriosis is an inflammatory disease with predominance of immunosuppressive M2 macrophages in the pelvic cavity that could be involved in the pathology through support and immune escape of ectopic lesions. Mesenchymal stromal cells (MSC) are found in ectopic lesions, and MSC from nonendometriosis sources are known to induce M2 macrophages. Therefore, MSC were hypothesized to play a role in the pathology of endometriosis. The aim was to characterize the functional phenotype of MSC in ectopic and eutopic endometrium from women with endometriosis. Stromal cells from endometriotic ovarian cysts (ESCcyst) and endometrium (ESCendo) were examined if they exhibited a MSC phenotype. Then, ESC were phenotypically examined for protein and gene expression of immunosuppressive and immunostimulatory molecules. Finally, ESC were functionally examined for their effects on monocyte differentiation into macrophages. ESCcyst and ESCendo expressed MSC markers, formed colonies, and differentiated into osteoblasts and adipocytes. Phenotypically, ESCcyst were more immunosuppressive, with significantly higher expression of immunosuppressive molecules. Functionally, ESCcyst induced more spindle-shaped macrophages, with significantly higher expression of CD14 and CD163, both features of M2 macrophages. The results suggest that ESCcyst may be more immunosuppressive than ESCendo and may promote immunosuppressive M2 macrophages that may support growth and reduce immunosurveillance of ectopic lesions.

Mesenchymal Stromal Cells Support Endometriotic Stromal CellsIn Vitro

“…The effects of Ad-MSC on ESC cyst shown here suggest that they should not be considered as a potential therapy for endometriosis, because they may support the pathology of endometriosis by maintaining and increasing growth of ectopic endometrial tissue. Moreover, since MSC are present in ectopic lesions in endometriosis as confirmed by us [ 11 ] and others [ 12 ], this indicates that MSC are likely involved in the pathogenesis of endometriosis.…”

“…Previously, it has been found that autologous MSC are altered by the pathology of endometriosis [ 10 ]. In addition, we found that MSC from the ectopic (ESC cyst ) endometrium were phenotypically and functionally different from MSC from the eutopic (ESC endo ) endometrium in women with endometriosis suggesting that autologous MSC may be altered by the pathology [ 11 ]. Therefore, in the present study, we aimed to investigate the effects of allogeneic Ad-MSC on endometriosis-derived cells in vitro as the first step of a long-term goal of developing a potential therapy for endometriosis.…”

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

“…Stromal cells derived from ovarian endometrioma were found to express markers of mesenchymal stromal cells (MSCs), formed colony forming units and exhibited multipotency suggesting characteristics of mesenchymal stem-like cells. The MSCs from endometriomas promoted differentiation of monocytes to spindle shaped pro-repair/immunosuppressive macrophages in vitro (50). The results suggest that MSC influence macrophages such that they exhibit an immunosuppressive phenotype and support lesion growth.…”

“…Notably, stem cells and macrophages are known to have a reciprocal relationship whereby stem cells can contribute to macrophage activation and phenotype during regenerative processes and macrophages can dictate accumulation of progenitor/stem cell-like cells (49). In endometriosis, mesenchymal stem-like cells promote macrophages to adopt a pro-repair phenotype (50) but further studies regarding the relationship between stem cells and macrophages in endometriosis are currently limited. Müllerianosis (müllerian rests; normal endometrial, endosalpingeal, and endocervical tissue) predicts that developmentally displaced tissue are incorporated into normal organs during organogenesis (51).…”

Biological characteristics of endometriotic mesenchymal stem cells isolated from ectopic lesions of patients with endometriosis

“…Interestingly, the immunomodulatory potential of menstrual blood-derived EnSCs has been verified; menstrual blood-derived EnSCs not only suppressed the lymphocyte proliferation and inflammatory cytokine secretion in an animal model of critical limb ischaemia but also modulated cytokine profiles and regulated immune cells to improve liver function and attenuate pathological changes in an animal model of acute liver injury [ 42 – 44 ] Therefore, to address whether the immunomodulatory potential of EnSC-EM-EC differs from EnSC-Control, Nair et al reported in 2014 that EnSC-EM-EC exhibited an immune phenotype distinct from that of EnSC-Control; this phenotype included increased levels of TLRs, collectins and pro-inflammatory cytokines, which may be responsible for the reduced immunosuppressive activity of ectopic MSCs [ 35 ]. In contrast, in 2017, Abomaray et al demonstrated that EnSC-EM-EC may be more immunosuppressive than EnSC-Control and may promote the activity of immunosuppressive M2 macrophages that support the growth of and reduce immunosurveillance in ectopic lesions [ 45 ]. Furthermore, in contrast to the findings of Nair et al, our in vitro results indicated that both types of EnSCs produced large amounts of pro-inflammatory cytokines (L-6, IL-8 and IFN-γ) and MCP-1 and that EnSC-EM-EC produced slightly but nonsignificantly greater amount of pro-inflammatory cytokines than EnSC-Control.…”