Hyaluronan/CD44 and the Early Endometriotic Lesion

描述(申请人提供)：子宫内膜异位症是一种常见的妇科疾病，影响高达10%的育龄妇女。尽管这种疾病的发病率很高，症状也很严重，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，月经子宫内膜的碎片通过输卵管逆行进入腹膜腔，在那里它们附着并生长在腹膜表面。我们最近利用人腹膜或间皮细胞单层外植体和机械分散的子宫内膜细胞建立了一种新的体外子宫内膜异位症模型。我们的研究表明，子宫内膜碎片能迅速附着于完整培养的腹膜间皮细胞上。ESC和EEC在接种后1小时内均与腹膜间皮细胞黏附。最近的研究表明，间皮细胞产生的线性二糖聚合物透明质酸和调节细胞间相互作用的多功能1型跨膜糖蛋白CD44参与了卵巢癌和胃癌细胞与间皮细胞的结合。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。大量使用非子宫内膜细胞类型的证据表明，CD44异构体的表达、CD44细胞表面密度和CD44糖基化/糖胺糖化模式不同地影响细胞对透明质酸的黏附能力。我们的初步数据表明，子宫内膜异位症患者的子宫内膜上皮细胞与间皮细胞有更强的结合能力，并且与间皮细胞的结合依赖于CD44的细胞表面密度。这些观察结果再加上CD44亚型在人子宫内膜中的不同表达，使我们推测CD44的定性和定量表达调节了子宫内膜细胞与腹膜间皮细胞的黏附能力。本文描述的新实验将表征患有和不患有子宫内膜异位症的妇女子宫内膜细胞中CD44细胞的异构体表达、细胞表面密度和糖基化/糖胺糖化模式。这将提高我们对子宫内膜异位症早期病变发展的认识。这些发现应该使我们能够根据子宫内膜细胞CD44的特征来预测女性患子宫内膜异位症的风险，并提出预防这种疾病的新方法。

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.