Department of Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, HH-333, Stanford, California 94305-5317, USA.
Endocrinology. 2012 Mar;153(3):1063-9. doi: 10.1210/en.2011-1826. Epub 2012 Jan 31.
Despite the vital physiological role of endometrial regeneration during the menstrual cycle and the various pathological implications of abnormal growth of endometrial epithelial cells, the local factors and regulatory mechanisms involved in endometrial regeneration and growth have not been well characterized. Here, we examine the pattern, hormone dependence, and potential functions of Wnt7a (wingless-type MMTV integration site family member 7a), which is known to play a critical role in the formation of the mouse endometrial epithelium during embryonic development, in both human and artificially cycling rhesus macaque endometrium, and using a potent Wnt-antagonist in a mouse model of endometrial regeneration. Wnt7a transcript levels were examined using quantitative real-time PCR and in situ hybridization, and immunohistochemistry was performed to detect Ki-67 and 3,5-bromodeoxyuridine. Stringent, fully conditional Wnt inhibition was achieved by adenoviral expression of Dickkopf-1 during artificial endometrial regeneration in mice. In macaques, Wnt7a expression was confined to the newly formed luminal epithelium (LE) and upper glands during the postmenstrual repair phase. The signal increased in the LE during the proliferative phase but decreased in the upper glands and was undetectable in the glands by the late proliferative phase. Interestingly, Wnt7a was completely suppressed in the LE and remained undetectable in other cell types after 7 d of progesterone treatment. The pattern of Wnt7a expression in the human endometrium was similar to that in macaques. Blockade of Wnt signaling during endometrial regeneration in mice resulted in a dramatic delay in reepithelialization and degeneration of glands and LE. These results strongly suggest, for the first time, a role for Wnt7a in postmenstrual regeneration and proliferation of endometrial glands and LE in primates, and its dramatic suppression by progesterone is likely essential for secretory transformation of the epithelium.
尽管子宫内膜在月经周期中的再生具有重要的生理作用，且子宫内膜上皮细胞异常生长具有多种病理意义，但涉及子宫内膜再生和生长的局部因素和调节机制尚未得到很好的描述。在这里，我们研究了 Wnt7a（无翅型 MMV 整合位点家族成员 7a）的模式、激素依赖性和潜在功能，已知其在胚胎发育过程中对小鼠子宫内膜上皮的形成起着关键作用，我们还使用一种有效的 Wnt 拮抗剂在子宫内膜再生的小鼠模型中研究了 Wnt7a。使用定量实时 PCR 和原位杂交技术检测 Wnt7a 转录物水平，并进行免疫组织化学检测以检测 Ki-67 和 3,5-溴脱氧尿苷。通过在小鼠中表达 Dickkopf-1 进行严格、完全条件的 Wnt 抑制，从而实现人工子宫内膜再生。在猕猴中，Wnt7a 表达仅限于月经后修复期的新形成的腔上皮 (LE) 和上部腺体。在增殖期，信号在 LE 中增加，但在上部腺体中减少，在增殖后期，腺体中无法检测到信号。有趣的是，在黄体期 7 天后，Wnt7a 在 LE 中完全被抑制，在其他细胞类型中仍无法检测到。人类子宫内膜中 Wnt7a 的表达模式与猕猴相似。在小鼠子宫内膜再生过程中阻断 Wnt 信号导致再上皮化和腺体和 LE 退化明显延迟。这些结果首次强烈表明，Wnt7a 在灵长类动物月经后的再生和子宫内膜腺体和 LE 的增殖中起作用，其被孕激素的显著抑制可能是上皮分泌转化所必需的。
