Endometrial stem cell-derived granulocyte-colony stimulating factor attenuates endometrial fibrosis via sonic hedgehog transcriptional activator Gli2
Endometrial stem cell-derived granulocyte-colony stimulating factor attenuates endometrial fibrosis via sonic hedgehog transcriptional activator Gli2
复制标题
子宫内膜干细胞衍生的粒细胞集落刺激因子通过 sonic eager 转录激活剂 Gli2 减轻子宫内膜纤维化
DOI：
10.1093/biolre/ioy005
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发表时间：
2018-04-01
影响因子：
3.6
通讯作者：
Zhang, Songying
中科院分区：
文献类型：
--
作者：
Lin, Xiaona;Zhang, Yanling;Zhang, Songying
宫腔粘连（IUA）的特征是子宫内膜纤维化，最终导致月经异常、不孕和反复流产。Shh/Gli 2通路在组织纤维发生和再生中起着关键作用; Gli 2活化在各种组织中诱导促纤维发生作用，例如肝脏和肾脏。然而，Gli 2在子宫内膜纤维化中的作用仍然未知。本研究的目的是验证激活的Gli 2促进子宫内膜纤维化的假设。与正常子宫内膜样本和轻度IUA样本相比，中重度IUA患者的子宫内膜样本显示Gli 2表达显著增强。过度活跃的Gli 2质粒转染诱导更高的纤维化相关蛋白的表达，而阻断Gli 2信号与cyclopamine引起相反的效果在增生性基质细胞（ESCs），包括诱导细胞周期停滞。月经来源的干细胞条件培养基（MenSCs-CM）通过降低Gli 2蛋白水平和通过粒细胞集落刺激因子（G-CSF）引起ESC细胞周期停滞来减少子宫内膜纤维化。用G-CSF抗体中和后，该作用减弱。Gli 2过表达降低了MenSC-CM和G-CSF对体外纤维化和细胞周期进展的影响。在小鼠肝纤维化模型中也观察到G-CSF的抗纤维化作用。这些发现表明Gli 2信号通路促进子宫内膜纤维化，并且通过MenSC分泌的G-CSF抑制Gli 2可能对控制子宫内膜纤维化具有治疗价值。
Intrauterine adhesion (IUA) is characterized by endometrial fibrosis, which ultimately leads to menstrual abnormalities, infertility, and recurrent miscarriages. The Shh/Gli2 pathway plays a critical role in tissue fibrogenesis and regeneration; Gli2 activation induces profibrogenic effects in various tissues, such as the liver and kidney. However, the role of Gli2 in endometrial fibrosis remains unknown. The purpose of this study was to test the hypothesis that activated Gli2 promotes endometrial fibrosis. Endometrial samples from moderate and severe IUA patients exhibited significantly enhanced expression of Gli2 compared with normal endometrial samples and mild IUA samples. Transfection with overactive Gli2 plasmids induced higher fibrosis-related protein expression, while blocking Gli2 signaling with cyclopamine caused the opposite effect in endometriotic stromal cells (ESCs), including inducing cell-cycle arrest. Menstrual-derived stem cell conditioned medium (MenSCs-CM) reduced endometrial fibrosis by reducing Gli2 protein levels and causing cell-cycle arrest in ESCs through granulocyte-colony stimulating factor (G-CSF). The effect was weakened after neutralization with a G-CSF antibody. Gli2 overexpression reduced the effects of MenSC-CM and G-CSF on fibrosis and cell-cycle progression in vitro. The antifibrotic effect of G-CSF was also observed in murine model. These findings demonstrate that Gli2 signaling promotes endometrial fibrosis, and the inhibition of Gli2 through MenSCs-secreted G-CSF may be of therapeutic value for managing endometrial fibrosis.Summary SentenceG-CSF secreted by endometrial stem cell could attenuate endometrial fibrosis via Gli2 protein.