Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, 361102, Xiamen, Fujian, China.
Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Nanjing University Medical School, 210093, Nanjing, Jiangsu, China.
Cell Death Dis. 2022 Sep 2;13(9):757. doi: 10.1038/s41419-022-05184-y.
Ciliated and secretory cells are two major cell types that comprise the oviduct epithelia. Accumulating evidences support a role of oviductal multiciliated epithelia for embryo transport, however the mechanisms underlying this specialized cell type differentiation remain elusive. Here, we report that CDC42 depletion in oviduct epithelia hampers the morphogenesis of multiciliated cell, and results in embryo retention, leading to early pregnancy failure. Utilizing the oviduct organoid model, we further observed that CDC42 guides secretory cells transition into multiciliated cells independent of its GTPase activity and the well-known Notch pathway. Further exploration uncovered the AKT as a novel indispensable regulator for multiciliated cells differentiation, whose activity was maintained by CDC42 through interacting with the p110β. Consistently, re-activating AKT partially incites multiciliated cells differentiation in Cdc42 knockout oviductal organoids. Finally, low levels of CDC42 and phospho-AKT with reduced multiciliated cells in the oviduct are observed in women with ectopic pregnancy. Collectively, we provide previously unappreciated evidence that CDC42-AKT signaling is a critical determinant for morphogenesis of oviduct multiciliated cell, which possesses the clinical application in understanding the pathology of ectopic pregnancy and facilitating the development of prevention strategies.
纤毛细胞和分泌细胞是构成输卵管上皮的两种主要细胞类型。越来越多的证据支持输卵管多纤毛上皮在胚胎运输中的作用，但这种特化细胞类型分化的机制仍不清楚。在这里，我们报告称，CDC42 在输卵管上皮中的耗竭会阻碍多纤毛细胞的形态发生，并导致胚胎滞留，从而导致早期妊娠失败。利用输卵管类器官模型，我们进一步观察到 CDC42 通过不依赖其 GTPase 活性和众所周知的 Notch 途径引导分泌细胞向多纤毛细胞转化。进一步的探索揭示了 AKT 是多纤毛细胞分化的一个新的不可或缺的调节剂，其活性通过与 p110β 相互作用被 CDC42 维持。一致地，在 Cdc42 敲除的输卵管类器官中重新激活 AKT 可部分诱导多纤毛细胞分化。最后，在异位妊娠的女性中观察到输卵管中 CDC42 和磷酸化 AKT 水平降低，多纤毛细胞减少。总之，我们提供了以前未被认识到的证据，表明 CDC42-AKT 信号是输卵管多纤毛细胞形态发生的关键决定因素，这在理解异位妊娠的病理学和促进预防策略的发展方面具有临床应用价值。
