mTORC1 signaling pathway integrates estrogen and growth factor to coordinate vaginal epithelial cells proliferation and differentiation

Wan, Shuo; Sun, Yan; Fu, Jiamin; Song, Haiyan; Xiao, Zhi‐Qiang; Yang, Qian; Wang, Sanfeng; Yu, Gongwang; Feng, Peiran; Lv, Wenkai; Luo, Liang; Guan, Zerong; Liu, Feng; Zhou, Qinghua; Yin, Zhinan; Yang, Meixiang

doi:10.1038/s41419-022-05293-8

Cited by 8 publications

(8 citation statements)

References 58 publications

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Section: Resultsmentioning

confidence: 99%

“…During the estrous cycle, serum progesterone levels reach peak values at the diestrus stage and are lowest value at the proestrus stage, while serum estradiol levels are highest in the proestrus stage. 35 In response to E2 and P4, the endometrium undergoes extensive remodeling during each estrous cycle. 36,37 We wondered if the disturbed proliferation status in response to E2 and P4 observed in early pregnancy in our E-OEx mice was already occurring during the estrous cycle.…”

Section: The Ge Is More Sensitive To Estrogen In the E-oex Micementioning

confidence: 99%

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Aberrant activation of Notch1 signaling in the mouse uterine epithelium promotes hyper‐proliferation by increasing estrogen sensitivity

Madhavan

Wei

et al. 2023

The FASEB Journal

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In mammals, the endometrium undergoes dynamic changes in response to estrogen and progesterone to prepare for blastocyst implantation. Two distinct types of endometrial epithelial cells, the luminal (LE) and glandular (GE) epithelial cells play different functional roles during this physiological process. Previously, we have reported that Notch signaling plays multiple roles in embryo implantation, decidualization, and postpartum repair. Here, using the uterine epithelial‐specific Ltf‐iCre, we showed that Notch1 signaling over‐activation in the endometrial epithelium caused dysfunction of the epithelium during the estrous cycle, resulting in hyper‐proliferation. During pregnancy, it further led to dysregulation of estrogen and progesterone signaling, resulting in infertility in these animals. Using 3D organoids, we showed that over‐activation of Notch1 signaling increased the proliferative potential of both LE and GE cells and reduced the difference in transcription profiles between them, suggesting disrupted differentiation of the uterine epithelium. In addition, we demonstrated that both canonical and non‐canonical Notch signaling contributed to the hyper‐proliferation of GE cells, but only the non‐canonical pathway was involved with estrogen sensitivity in the GE cells. These findings provided insights into the effects of Notch1 signaling on the proliferation, differentiation, and function of the uterine epithelium. This study demonstrated the important roles of Notch1 signaling in regulating hormone response and differentiation of endometrial epithelial cells and provides an opportunity for future studies in estrogen‐dependent diseases, such as endometriosis.

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Section: Resultsmentioning

confidence: 99%

Section: The Ge Is More Sensitive To Estrogen In the E-oex Micementioning

confidence: 99%

Aberrant activation of Notch1 signaling in the mouse uterine epithelium promotes hyper‐proliferation by increasing estrogen sensitivity

Madhavan

Wei

et al. 2023

The FASEB Journal

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“…In recent studies, Zheng et al 20 . and Wan et al 21 . revealed the m 6 A-mediated mechanisms for ensuring normal progesterone and estrogen signaling during embryo implantation.…”

Section: Recent Progress In Embryo Implantation Research In Humans An...mentioning

confidence: 99%

“…Loss of m 6 A modifications causes estrogen dominance and progesterone resistance. Specifically, m 6 A-seq analysis identified m 6 A modifications in the 3′ untranslated region of several estrogen-responsive genes, mRNAs of which exhibited increased stability upon METTL3 depletion 21 . In addition to posttranscriptional regulation, steroid nuclear receptor activities are also regulated by posttranslational modifications, such as phosphorylation and ubiquitination 22,23 .…”

Section: Recent Progress In Embryo Implantation Research In Humans An...mentioning

confidence: 99%

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

Bao,

Wang

2024

Maternal Fetal Med

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This review aimed to summarize the major progress in maternal-fetal medicine achieved by Chinese scientists in recent years. PubMed was systematically searched from January 2020 to November 2023. Publications that reported the progress in embryo implantation, placentation, and parturition made by Chinese scientists in the last 3 years were selected. The milestone events during gestation, embryo implantation, endometrial decidualization, placentation, and parturition are pivotal to a successful pregnancy. Embryo implantation requires intricate interactions between implantation-competent blastocysts and receptive endometrium. To adapt to pregnancy, endometrial stromal cells transform into specialized decidual cells, which occur spontaneously under the influence of ovarian hormones in humans but require the presence of embryos in mice. With embryonic development, the placenta forms to support fetal growth until parturition. The maternal-fetal interface is composed of diverse cell types, including endometrial decidual cells, placental trophoblast cells, endothelial cells, and various immune cells, a sophisticated interplay among which contributes to the maintenance of pregnancy. Near term, the uterus transitions from quiescence to contractility, in preparation for delivery. Disruptions to these events lead to pregnancy-related disorders such as repeated implantation failure, recurrent pregnancy loss, preeclampsia, fetal growth restriction, preterm birth, and infertility. In recent years, Chinese scientists have made prominent achievements in basic research on the aforementioned pregnancy events. Chinese scientists have made remarkable contributions to reproductive biology and maternal-fetal medicine research in recent years, highlighting future research directions in this field.

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“…techniques [1,[6][7][8], which identified key markers but not provide sufficient dynamic spatiotemporal information of the epithelium's differentiation process. In recent years, genetic rodent models leveraging advanced gene editing techniques, alongside surgically induced ovariectomy (OVX) models in mice and rats, have shed new light on the differentiation mechanisms of the female reproductive tract epithelium [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Molecular stratification of human fetal vaginal epithelium by spatial transcriptome analysis

Ye,

Jiang,

Zhu

et al. 2024

Preprint

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The human vaginal epithelium is a crucial component in numerous reproductive processes and serves as a vital protective barrier against pathogenic invasion. Despite its significance, a comprehensive exploration of its molecular profiles, including molecule expression and distribution across its multiple layers, remains elusive. In our study, we undertook a spatial transcriptomic analysis within the vaginal wall of human fetuses to fill this knowledge gap. We successfully categorized vaginal epithelium into four distinct zones based on their transcriptomic profiles and anatomical features. This approach unveiled unique transcriptomic signatures within these regions, allowing us to identify differentially expressed genes and uncover novel markers for distinct regions of the vaginal epithelium. Additionally, our findings have highlighted the varied expression of KRT genes across different zone of the vaginal epithelium, with a gradual shift in expression patterns observed from the basal layer to the surface/superficial layer. This suggests a potential differentiation trajectory of human vaginal epithelium, shedding light on the dynamic nature of this tissue. Furthermore, abundant biological processes were found to be enriched in the basal zone by the KEGG pathway analysis, indicating an active state of the basal zone cells. Subsequently, the expression of latent stem cell markers in the basal zone were identified. In summary, our research provides crucial understanding of human vaginal epithelial cells and the complex mechanisms of the vaginal mucosa, with potential applications in vaginal reconstruction and drug delivery, making this atlas a valuable tool for future research in women's health and reproductive medicine.

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mTORC1 signaling pathway integrates estrogen and growth factor to coordinate vaginal epithelial cells proliferation and differentiation

Cited by 8 publications

References 58 publications

Aberrant activation of Notch1 signaling in the mouse uterine epithelium promotes hyper‐proliferation by increasing estrogen sensitivity

Aberrant activation of Notch1 signaling in the mouse uterine epithelium promotes hyper‐proliferation by increasing estrogen sensitivity

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

Molecular stratification of human fetal vaginal epithelium by spatial transcriptome analysis

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