Polotsky Alex J, Zhu Liyin, Santoro Nanette, Pollard Jeffrey W
Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Hum Reprod. 2009 Aug;24(8):1960-7. doi: 10.1093/humrep/dep115. Epub 2009 Apr 29.
In mouse endometrium, glycogen synthase kinase-3beta (GSK3beta) is a key enzyme controlling nuclear localization of cyclin D1. We developed a functional model of xenografted human endometrium to test whether similar mechanisms are operative in the human by using Lithium chloride (LiCl), an inhibitor of GSK3beta.
Human endometrial samples were obtained from normal volunteers, then implanted under the kidney capsule of nude mice, and treated with estradiol-17beta (E2) or LiCl. Xenografts were assessed for protein expression of MKI-67, mini-chromosome maintenance protein-2, estrogen receptor (ER), progesterone receptor (PR) and cyclin D1.
Both E2 and LiCl induced a robust proliferative response in the epithelium. Only lithium treatment produced clear nuclear localization of cyclin D1 consistent with the proliferative response observed. Regenerated endometrium had detectable ER and PR expression.
Xenografted human endometrium provides a dynamic model of uterine biology. Administration of LiCl in the absence of E2 induced epithelial proliferation, supporting the hypothesis that human and murine endometrial proliferation may share key regulatory pathways. These data suggest a possible link between the increased menstrual disturbances in women with affective disorders taking lithium and the consequent potential for the development of endometrial proliferative disorder.
在小鼠子宫内膜中，糖原合酶激酶-3β（GSK3β）是控制细胞周期蛋白D1核定位的关键酶。我们建立了一个人子宫内膜异种移植功能模型，以通过使用GSK3β抑制剂氯化锂（LiCl）来测试人类是否存在类似机制。
从正常志愿者获取人子宫内膜样本，然后将其植入裸鼠肾包膜下，并用17β-雌二醇（E2）或LiCl进行处理。评估异种移植组织中MKI-67、微小染色体维持蛋白-2、雌激素受体（ER）、孕激素受体（PR）和细胞周期蛋白D1的蛋白表达。
E2和LiCl均在上皮细胞中诱导了强烈的增殖反应。只有锂处理使细胞周期蛋白D1出现明确的核定位，这与观察到的增殖反应一致。再生的子宫内膜有可检测到的ER和PR表达。
人子宫内膜异种移植提供了一个子宫生物学的动态模型。在没有E2的情况下给予LiCl可诱导上皮细胞增殖，支持人和小鼠子宫内膜增殖可能共享关键调节途径的假说。这些数据表明，患有情感障碍的女性服用锂后月经紊乱增加与随后发生子宫内膜增殖性疾病的潜在可能性之间可能存在联系。
