CoChat
Sign Up
Cited by 124Endometriosis Research and TreatmentTGF-β signaling in diseasesUterine Myomas and Treatments

Transforming growth factor β1 signaling coincides with epithelial–mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice

Shen, Minhong, Liu, Xishi, Zhang, Hongqi, Guo, Sun-Wei·2015·Human Reproduction
DOI 10.1093/humrep/dev314
Open this paper in CoChat — free account

Abstract

STUDY QUESTION: Do platelets have any role in the development of adenomyosis? SUMMARY ANSWER: Activated platelets coincide with the release of transforming growth factor (TGF)-β1 and induction of the TGF-β/Smad signaling pathway as well as evidence of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in a mouse model of adenomyosis, resulting ultimately in fibrosis, as in adenomyosis. WHAT IS KNOWN ALREADY: Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis, but this was based primarily on cross-sectional observation. It is unclear as to whether adenomyotic lesions and their microenvironment have the machinery to promote EMT and FMT, resulting ultimately in fibrosis. There has not been any published study on the role of platelets in the development of adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which implicates the involvement of platelets and constitutes an environment conducive for fibrogenesis. STUDY DESIGN, SIZE, DURATION: Adenomyosis was induced in 28 female ICR mice by neonatal dosing of tamoxifen. Another 32 were neonatally dosed without tamoxifen. These mice were sacrificed serially and their tissue samples were subsequently evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female ICR mice with and without induced adenomyosis were sacrificed in batch at 5, 10, 15, 42 and 60 days of age. The depth of myometrial infiltration of endometrial tissues was assessed and immunohistochemistry analysis of biomarkers of EMT and FMT, as well as TGF-β1, phosphorylated Smad3 (p-Smad3) and markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits was performed in ectopic (for adenomyotic mice) and eutopic (controls) endometrial tissue samples. Masson trichrome and Van Gieson stainings were performed to quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. MAIN RESULTS AND THE ROLE OF CHANCE: While TGF-β1 immunoreactivity was consistently low in control endometrium, its level was increased dramatically starting from Day 10, along with the extent of platelet aggregation. Staining for TGF-β1 and p-Smad3 increased progressively as adenomyosis progressed, along with markers for proliferation, angiogenesis and ECM deposits. Consistently, staining of vimentin (a marker for stromal or mesenchymal cells) was also increased while that of E-cadherin (a marker for epithelial cells) was reduced. PR-B staining also decreased progressively. Starting from Day 42, α-SMA staining, a marker for myofibroblasts, was elevated in lesions, while in control endometrium, it was negative. Concomitantly, the extent of fibrosis also was increased. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of histochemistry and immunohistochemistry analyses only and the lack of intervention. WIDER IMPLICATIONS OF THE FINDINGS: Like their endometriotic counterpart, adenomyotic lesions and their microenvironment may contain all the necessary molecular machinery to promote fibrogenesis. Platelet-induced activation of the TGF-β/Smad signaling pathway may be a driving force in EMT and FMT in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and as such, platelets play critical roles in the development of adenomyosis. It suggests the potential for the use of anti-platelet therapy in the treatment of adenomyosis, and also opens a new venue for developing novel biomarkers for diagnostic or prognostic purposes. STUDY FUNDING/COMPETING INTERESTS: Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

Integrity signals

Registry

Crossref · 10.1093/humrep/dev314

Cites

102 of 102 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Shen, M., Liu, X., Zhang, H., & Guo, S.-W.
Affiliations
  • Fudan University (CN)
  • Shanghai Medical College of Fudan University (CN)
Corresponding author
Guo, Sun-Wei
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2015-12-20
Volume
31
Issue
2
Pages
dev314
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/dev314
OpenAlex
W2298855487
Cited by
124
References
102
Citations by year
2026: 3 · 2025: 6 · 2024: 11 · 2023: 10 · 2022: 11 · 2021: 9 · 2020: 25 · 2019: 11 · 2018: 15 · 2017: 12 · 2016: 11
FWCI
14.49
Type
journal article
Language
en
Open access
closed
Locations
  • Human Reproduction (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Science Foundation of China (2013ZYJB0019)
  • Shanghai Municipal Commission of Health and Family Planning
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
Keywords
adenomyosis, TGF-β1, epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, platelets, TGF-β/Smad signaling, Smad3 phosphorylation, endometrial fibrosis, myometrial invasion, extracellular matrix, angiogenesis
MeSH terms
Animals, Endometrium, Female, Fibroblasts, Immunohistochemistry, Mice, Inbred ICR, Neovascularization, Pathologic, Platelet Aggregation, Receptors, Progesterone, Vimentin, Signal Transduction, Biomarkers, Cadherins, Cell Proliferation, Mice, Smad3 Protein, Transforming Growth Factor beta1, Cell Transdifferentiation, Myofibroblasts, Epithelial-Mesenchymal Transition, Adenomyosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review