SMAD7 的表达减少以及随之而来的自噬减少会促进子宫内膜基质-肌成纤维细胞转化和纤维化。

IF 3.6 2区 医学 Q2 DEVELOPMENTAL BIOLOGY Molecular human reproduction Pub Date : 2024-10-12 DOI:10.1093/molehr/gaae036
Min Yong, Honggui Zhou, Yuhua Zeng, Yuqin Yao, Hongtao Zhu, Jianguo Hu
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引用次数: 0

摘要

异常的自噬和转化生长因子-β(TGFβ)-SMAD3/7信号通路在宫腔内粘连(IUA)的发生中起着重要作用;然而,其确切的内在机制仍不清楚。在这项研究中,我们利用IUA患者组织和SMAD7条件性基因敲除小鼠来检测SMAD7是否通过调节自噬和TGFβ-SMAD3信号通路影响IUA。我们采用多种技术检测了p-SMAD3、SMAD7、自噬和纤维化相关蛋白、自噬通量以及SMAD3结合位点分析。IUA患者的子宫内膜组织显示出较低的SMAD7表达水平。在子宫内膜基质细胞中,沉默SMAD7会抑制自噬通量,而过量表达SMAD7则会促进自噬通量。这种由SMAD7介导的自噬通量调节着基质-肌成纤维细胞的转变,而这些表型受TGFβ-SMAD3信号通路的调节。SMAD3直接与转录因子EB(TFEB)的3'-非翻译区结合并抑制其转录。SMAD7 通过抑制 SMAD3 促进自噬通量,从而促进 TFEB 的表达。 在 SMAD7 条件性基因敲除小鼠中,子宫内膜表现出纤维化表型。同时,自噬通量受到抑制。在使用自噬激活剂雷帕霉素后,这种子宫内膜纤维化表型得到了部分逆转。SMAD7的缺失会通过TGFβ-SMAD3途径抑制自噬通量,从而促进子宫内膜纤维化。因此,本研究揭示了 IUA 的潜在治疗靶点。
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Reduced expression of SMAD7 and consequent reduction of autophagy promotes endometrial stromal-myofibroblast transition and fibrosis.

Abnormal autophagy and the transforming growth factor-β (TGFβ)-SMAD3/7 signaling pathway play an important role in the development of intrauterine adhesions (IUAs); however, the exact underlying mechanisms remain unclear. In this study, we used IUA patient tissue and SMAD7 conditional knockout mice to detect whether SMAD7 effected IUA via regulation of autophagy and the TGFβ-SMAD3 signaling pathway. We applied a combination of techniques for the detection of p-SMAD3, SMAD7, autophagy and fibrosis-related proteins, autophagic flux, and analysis of the SMAD3 binding site. Endometrial tissue of patients with IUA exhibited lower expression levels of SMAD7. In endometrial stromal cells, silencing of SMAD7 inhibited autophagic flux, whereas overexpressed SMAD7 promoted autophagic flux. This SMAD7-mediated autophagic flux regulates the stromal-myofibroblast transition, and these phenotypes were regulated by the TGFβ-SMAD3 signaling pathway. SMAD3 directly binds to the 3'-untranslated region of transcription factor EB (TFEB) and inhibits its transcription. SMAD7 promoted autophagic flux by inhibiting SMAD3, thereby promoting the expression of TFEB. In SMAD7 conditional knockout mice, the endometria showed a fibrotic phenotype. Simultaneously, autophagic flux was inhibited. On administering the autophagy activator rapamycin, this endometrial fibrosis phenotype was partially reversed. The loss of SMAD7 promotes endometrial fibrosis by inhibiting autophagic flux via the TGFβ-SMAD3 pathway. Therefore, this study reveals a potential therapeutic target for IUA.

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来源期刊
Molecular human reproduction
Molecular human reproduction 生物-发育生物学
CiteScore
8.30
自引率
0.00%
发文量
37
审稿时长
6-12 weeks
期刊介绍: MHR publishes original research reports, commentaries and reviews on topics in the basic science of reproduction, including: reproductive tract physiology and pathology; gonad function and gametogenesis; fertilization; embryo development; implantation; and pregnancy and parturition. Irrespective of the study subject, research papers should have a mechanistic aspect.
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