Hedgehog信号通路对滋养层细胞分化和浸润的调控及与早期流产的关系研究

滋养层细胞在胚胎着床和早期母胎界面的形成中起着重要作用，其分化和浸润母体蜕膜的异常将导致早期流产，严重伤害育龄妇女的身心健康。Hedghog(Hh)信号通路是一个保守的重要信号通路，参与多种器官形成和肿瘤发生。Hh信号通路对于滋养层细胞分化和浸润的作用和分子机制却未见报道。我们前期的研究表明Hh信号通路在小鼠囊胚的滋养外胚层细胞有特异的表达。Shh抑制剂则能促进滋养层细胞的浸润和迁移。在此基础上，本项目拟利用药理学方法、转基因技术和分子生物学手段研究Hh信号通路对小鼠囊胚发育、滋养层干细胞分化和滋养层细胞浸润的影响和分子机制。此外，通过比较正常人工流产和早期流产的绒毛组织中Hh信号通路的表达差异以及血液中Shh含量的差异，阐明Hh信号通路在早期流产中的异常表达原因和分子机制。通过本项目的研究将拓宽Hh信号通路的生理功能，并为早期流产的发病机理及临床治疗提供重要的理论支撑。

Trophoblasts, the specialized cells of the placenta, play a major role in implantation and formation of the maternal-fetal interface. Failures in human trophoblast development could be involved in early pregnancy loss. Hedgehog (Hh) signaling pathway functions as a conserved morphogen in various organs’ development and tumorigenesis in metazoans ranging from Drosophila to humans. However, whether and how the process of trophoblast development is regulated by Hh signaling remained elusive. Our previous study has investigated the underlying mechanisms of Hh signaling in trophoblast development. Immunofluorescence revealed the abundant expression of the main components of Hh pathway in the trophectoderm of blastocysts. Shh inhibition increased the motility of HTR8/SVneo cells, which tested by uncoated and Matrigel-coated Transwells. Furthermore, the expression level of Hh signaling was significantly higher in the early pregnancy loss placentas compared to the gestation age-matched normal placentas. Combining molecular, pharmacological, lentivirus and physiological approaches, we elucidate the detailed effects and underlying mechanism of Hh signaling in the pathogenesis of trophoblast development and early miscarriage. This study will provide with a new concept of Hh signaling in the physiology of pregnancy.