Habata Shutaro, Mamillapalli Ramanaiah, Ucar Abdullah, Taylor Hugh S
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 06510, USA.
Stem Cells Int. 2023 Jul 28;2023:1598127. doi: 10.1155/2023/1598127. eCollection 2023.
Endometriosis is a chronic inflammatory gynecological disorder regulated by estrogen and characterized by the growth of endometrial tissue outside the uterus. We have previously demonstrated that mesenchymal stem cells (MSCs) contribute directly to endometriosis. Here, we investigated an indirect effect; we hypothesized that MSCs may also impact the bone marrow (BM) by regulating bone marrow-derived inflammatory cells. Endometriosis was induced in mice by transplanting uterine tissue into recipient mice followed by BM transplant. Control or MSC conditioned BM was injected retro-orbitally. Direct administration of MSCs outside of the setting of BM conditioning did not alter endometriosis. Coculture of an undifferentiated macrophage cell line with MSCs in vitro led to a reduction of M1 and increased M2 macrophages as determined by fluorescence-activated cell sorting and western blot. Conditioning of BM with MSCs and transplantation into a mouse model inhibited endometriotic lesion development and reduced lesion volume by sevenfold compared to BM transplant without MSCs conditioning. Immunohistochemistry and immunofluorescence showed that MSC conditioned BM reduced the infiltration of macrophages and neutrophils into endometriotic lesions by twofold and decreased the proportion of M1 compared to M2 macrophages, reducing inflammation and likely promoting tissue repair. Expression of several inflammatory markers measured by quantitative real-time polymerase chain reaction, including tumor necrosis factor alpha and CXCR4, was decreased in the conditioned BM. Donor MSCs were not detected in recipient BM or endometriotic lesions, suggesting that MSCs actively program the transplanted BM. Taken together, these data show that individual characteristics of BM have an unexpected role in the development of endometriosis. BM remodeling and alterations in the inflammatory response are also potential treatments for endometriosis. Identification of the molecular basis for BM programing by MSCs will lead to a better understanding of the immune system contribution to this disease and may lead to new therapeutic targets for endometriosis.
子宫内膜异位症是一种由雌激素调节的慢性炎症性妇科疾病，其特征是子宫外子宫内膜组织的生长。我们之前已经证明间充质干细胞（MSC）直接促成了子宫内膜异位症。在此，我们研究了一种间接效应；我们假设MSC也可能通过调节骨髓来源的炎症细胞来影响骨髓（BM）。通过将子宫组织移植到受体小鼠中，随后进行骨髓移植，在小鼠中诱导子宫内膜异位症。将对照或MSC条件培养基经眶后注射。在没有骨髓预处理的情况下直接施用MSC不会改变子宫内膜异位症。体外将未分化的巨噬细胞系与MSC共培养导致通过荧光激活细胞分选和蛋白质印迹法测定的M1巨噬细胞减少和M2巨噬细胞增加。用MSC对骨髓进行预处理并移植到小鼠模型中可抑制子宫内膜异位症病变的发展，与未经MSC预处理的骨髓移植相比，病变体积减少了七倍。免疫组织化学和免疫荧光显示，与未进行MSC预处理的骨髓移植相比，MSC条件培养基可使巨噬细胞和中性粒细胞向子宫内膜异位症病变的浸润减少两倍，并降低M1与M2巨噬细胞的比例，减轻炎症并可能促进组织修复。通过定量实时聚合酶链反应测量的几种炎症标志物的表达，包括肿瘤坏死因子α和CXCR4，在条件培养基中降低。在受体骨髓或子宫内膜异位症病变中未检测到供体MSC，这表明MSC积极地对移植的骨髓进行编程。综上所述，这些数据表明骨髓的个体特征在子宫内膜异位症的发展中具有意想不到的作用。骨髓重塑和炎症反应的改变也是子宫内膜异位症的潜在治疗方法。确定MSC对骨髓编程的分子基础将有助于更好地理解免疫系统对这种疾病的贡献，并可能导致子宫内膜异位症的新治疗靶点。
