Hyaluronan/CD44 and the Early Endometriotic Lesion

描述（由申请人提供）：子宫内膜异位症是一种常见的妇科疾病，影响多达10%的育龄妇女。尽管发病率高，症状严重，但对子宫内膜异位症的发病机制知之甚少。一种被称为桑普森理论的理论认为，月经期子宫内膜的碎片通过输卵管逆行进入腹膜腔，在腹膜表面附着并生长。我们最近开发了一种新的子宫内膜异位症体外模型，使用人腹膜或间皮细胞单层和机械分散的子宫内膜细胞的外植体。我们的研究表明，子宫内膜碎片迅速粘附在完整的培养腹膜间皮上。ESC和EEC在镀后1小时内均粘附在腹膜间皮上。最近的研究表明，透明质酸（一种由间皮产生的线性双糖聚合物）和CD44（一种调节细胞间相互作用的多功能1型跨膜糖蛋白）参与了卵巢癌和胃癌细胞与间皮的结合。利用我们的模型，我们证明了透明质酸酶抑制子宫内膜细胞与间皮细胞的附着，这表明透明质酸/CD44也参与了子宫内膜异位症的发病机制。使用子宫内膜以外的细胞类型的大量证据表明，CD44异构体表达、CD44细胞表面密度和CD44糖基化/糖胺糖基化模式对细胞粘附透明质酸的能力有不同的影响。我们的初步数据表明，子宫内膜异位症女性的子宫内膜上皮细胞与间皮细胞的结合能力更强，而与间皮细胞的结合依赖于细胞表面CD44的密度。这些观察结果加上CD44亚型在人子宫内膜中的可变表达，使我们假设CD44的定性和定量表达调节子宫内膜细胞粘附于腹膜间皮的能力。本文描述的新实验将表征CD44细胞异构体表达、细胞表面密度和糖基化/糖胺糖基化模式在患有和未患有子宫内膜异位症的女性子宫内膜细胞中。这将增强我们对早期子宫内膜异位症病变发展的理解。研究结果使我们能够根据子宫内膜细胞CD44特征预测女性发生子宫内膜异位症的风险，并提出预防该疾病的新方法。

DESCRIPTION (provided by applicant): Endometriosis is a common gynecologic disease affecting up to 10% of reproductive-age women. Despite this high prevalence and the severe symptoms associated with the disease, little is known about the pathogenesis of endometriosis. One theory, known as Sampson's theory, proposes that fragments of menstrual endometrium pass retrograde through the fallopian tubes into the peritoneal cavity where they attach and grow on peritoneal surfaces. We recently developed a novel in vitro model of endometriosis using explants of human peritoneum or mesothelial cell monolayers and mechanically dispersed endometrial cells. Our studies demonstrate that endometrial fragments rapidly adhere to intact cultured peritoneal mesothelium. Both ESC and EEC adhere to peritoneal mesothelium within one hour of plating. Recent studies suggest that hyaluronan, a linear disaccharides polymer produced by mesothelium, and CD44, a multifunctional type 1 transmembrane glycoprotein that regulates cell-cell interactions, are involved in the binding of ovarian cancer and gastric cancer cells to mesothelium. Using our model, we demonstrated that hyaluronidase inhibits attachment of endometrial cells to mesothelial cells suggesting that hyaluronan/CD44 is also involved in the pathogenesis of endometriosis. A significant body of evidence using cell types other than endometrial suggests that the CD44 isoform expression, CD44 cell surface density, and CD44 glycosylation/glycosaminoglycanation pattern differentially affect a cells ability to adhere to hyaluronan. Our preliminary data demonstrate that endometrial epithelial cells from women with endometriosis have a greater ability to bind to mesothelial cells and that binding to mesothelial cells is dependent on the cell surface density of CD44. These observations coupled with the variable expression of CD44 isoforms in human endometrium lead us to hypothesize that the qualitative and quantitative expression of CD44 regulates the ability of endometrial cells to adhere to peritoneal mesothelium. The novel experiments described herein will characterize CD44 cell isoform expression, cell surface density and glycosylation/glycosaminoglycanation patterns in endometrial cells of women with and without endometriosis. This will enhance our understanding of the development of the early endometriotic lesion. The findings should enable us to predict a woman's risk of developing endometriosis based on endometrial cell CD44 characteristics and suggest new approaches to prevent the disease.