In this study, the administration of ASCs was found to significantly inhibit the growth of endometriosis-like lesions. In addition, ASCs displayed homing potential to integrate into endometriosis-like lesions, and suppressed the proliferation of endometriotic epithelial cells as well as the interstitial stromal reaction in a preclinical murine model of endometriosis. ASC infusion also decreased pro-inflammatory and pro-fibrotic cytokine expression but did not alter the expression of anti-inflammatory cytokines, matrix metalloproteases, angiogenetic factors, or estrogen and progesterone receptors.
Endometrial stem cells, which are located in the basalis layer, differentiate into the endometrial stroma, epithelium, and endothelium [39]. After the infusion of bone-marrow cells with mTert-GFP or Ch β-actin GFP, all GFP-positive cells in the endometrium are immune cells, including T cells and macrophages, suggesting that bone-marrow stem cells do not contribute to endometrial cell lineages [40]. In this study, infused ASCs were primarily detected in the endometriosis-like lesions, suggesting that they transdifferentiate into immune cells and help attenuate the stromal reaction in endometriosis-like lesions. Given that ASC administration significantly suppressed the thickness of the interstitial stroma and expression of pro-inflammatory and pro-fibrotic cytokines, it is plausible that ASCs, which were integrated into the institutional stromal tissues, suppress the expression of pro-inflammatory and pro-fibrotic cytokines that exacerbate the fibrotic changes in endometriosis. Indeed, ASC treatment significantly reduced the total number as well as the total weight and surface area of endometriosis-like lesions.
II-6 levels are elevated in the peritoneal fluid, endometriotic lesions, and serum from women with endometriosis [41, 42], and TGF-β1 is also upregulated in the peritoneal fluid and peritoneal membranes of women with endometriosis [43, 44]. In other preclinical models of endometriosis, it has been reported that the increase in IL-6 and TGF-β1 levels is attributable to the development of endometriosis-like lesions [13, 14]. MSCs, which retain immunomodulatory features and secrete trophic factors, have been utilized for treating various inflammatory and fibrotic diseases [45]. Several studies have demonstrated that MSC infusion attenuates fibrosis through the suppression of IL-6 or TGF-β1 expression [46, 47]. In this study, the administration of ASCs also reduced the expression of IL-6, MCP-1, Lif-1, and TGF-β1, accompanied by the attenuation of endometriosis-like lesions. Although the immunomodulatory and trophic factors remain to be unidentified [48], MCS infusion may represent a promising treatment for endometriosis.
Although MSCs have been previously shown to suppress the function of anti-inflammatory and angiogenic cytokines [48], such findings were not detected in this study. Here, the proliferation ratio of endometriotic epithelial cells in the treated groups was significantly suppressed and no clear differences in VEGF, MMP2, MMP9, IL-4, and IL-10 expression was found between the treated and control groups. In another experimental murine model of endometriosis, the infusion of anti-IL-6 antibody induced ectopic endometriotic epithelial cell atrophy [49]. Although it remains unclear why the growth of endometriotic epithelial cells was inhibited by ASC treatment, the suppression of IL-6 expression, which was mediated by ASC infusion, may have resulted in the decreased proliferation of endometriotic epithelial cells.
The safety and efficacy of infused MSCs have been validated by clinical trials in patients with a variety of diseases [45]. Moreover, ASC treatment had no influence on the expression of estrogen and progesterone receptors, suggesting that combination therapy involving hormonal therapy and MSC infusion would synergistically act to significantly attenuate endometriosis. Many women with endometriosis continue to suffer from severe dysmenorrhea, infertility, cancer, and other debilitating conditions. To overcome the incurable disorders associated with endometriosis, clinical trials investigating the potential of MSCs should be initiated for patients with endometriosis to preserve ovarian function and fertility.