Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial–mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation
Abstract
Smooth muscle metaplasia (SMM) and fibrotic tissues are frequently seen in endometriotic lesions, yet the mechanisms underlying their formation are poorly understood. In this study, we investigated the roles of activated platelets in driving epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in endometriosis. Through in vitro experimentations, we found that activated platelets, through the release of TGF-β1 and the induction of TGF-β/Smad signaling pathway, promoted EMT and FMT in endometriosis, resulting in increased cell contractility, collagen production, and ultimately to fibrosis. TGF-β blockade reversed these processes. Prolonged exposure of endometriotic stromal cells to activated platelets induced increased expression of α-SMA as well as markers of differentiated smooth muscle cells. Consequently, endometriotic lesions and their microenvironment contain all the necessary molecular machinery to promote SMM and fibrogenesis. Our results suggest that endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.
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Many non-endometriotic cells in the lesional microenvironment, such as platelets, macrophages, and nerve fibers, are actively involved in facilitating lesional development.
“many non-endometriotic cells in the lesional microenvironment, such as platelets21,23, macrophages19,24, and now nerve fibers25,26, are actively involved in facilitating lesional development.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [21]
Endometriotic lesions are essentially wounds undergoing repeated tissue injury and repair (ReTIAR).
“accumulating evidence suggests that endometriotic lesions are essentially wounds undergoing repeated tissue injury and repair (ReTIAR)19–22”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [21]
Our results are consistent with our previous report that platelets induce the TGF-β1/Smad3 signaling pathway in endometriotic cells.
“Our results are consistent with our previous report that platelets induce the TGF-β1/Smad3 signaling pathway in endometriotic cells21.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [21]
Many other cells in its microenvironment. Platelets, neutrophils, macrophages, and recently nerve fibers all have been identified to be accessories to aid and abet the lesional development.
“Platelets21,23, neutrophils69, macrophages19,24, and recently nerve fibers25,26 all have been identified to be accessories to aid and abet the lesional development.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [21]
Activated platelets induce the activation of the NF-κB signaling pathway and TGF-β1/Smad3 signaling pathway in endometriotic lesions.
“Activated platelets induce the activation of the NF-κB signaling pathway and TGF-β1/Smad3 signaling pathway in endometriotic lesions21.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [21]
Endometriotic lesions are wounds undergoing ReTIAR.
“the notion that endometriotic lesions are wounds undergoing ReTIAR is only appreciated very recently21,22,53”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [21]
As a result of ReTIAR, ectopic endometrium interacts with its microenvironment, activates TGF-β1/Smad3 signaling, experiences EMT and FMT, causing increased collagen production and cellular contractility and eventually fibrosis.
“As a result of this ReTIAR, the ectopic endometrium actively interacts with various cells in its microenvironment, activates the transforming growth factor (TGF)-β1/Smad3 signaling and experiences epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), causing increased collagen production and cellular contractility and eventually resulting in fibrosis22”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [22]
The results are consistent with the well documented roles of SP/CGRP and their receptors in wound healing and fibrogenesis.
“Viewed from the lens of the ReTIAR22, our results are consistent with the well documented roles of SP/CGRP and their receptors in wound healing and fibrogenesis.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [22]
Platelet-derived TGF-β1 promotes EMT, FMT, SMM and fibrogenesis in endometriotic lesions.
“We have previously shown that platelet-derived TGF-β1 promotes EMT, FMT, SMM and fibrogenesis in endometriotic lesions21,22,83.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [22]
Endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.
“Their results suggested that endometriotic lesions are wounds that undergo repeated injury and healing, highlighting the importance of platelets in the development of endometriosis.”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [48]
Endometriotic lesions and their microenvironment contain all the necessary molecular machinery to promote SMM and fibrogenesis.
“Zhang et al. (48) investigated with in vitro experimentations the roles of activated platelets in driving epithelial-to-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in endometriosis and concluded that endometriotic lesions and their microenvironment contain all the necessary molecular machinery to promote SMM and fibrogenesis.”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [48]
Some mesenchymal/mesothelial cells of the peritoneal cavity, of mesothelial repair after surgery, and in endometrium and endometriosis are directly derived from bone marrow.
“Some of these mesenchymal/ mesothelial cells of the peritoneal cavity (48), of the mesothelial repair after surgery (126) and in endometrium and endometriosis (127-131) are directly derived from bone marrow.”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [48]
Mesothelial-to-mesenchymal transition in the peritoneal cavity is well known, with a specific role of platelets.
“Mesothelial-to-mesenchymal transition in the peritoneal cavity is well known (124, 125) with a specific role of platelets (48).”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [48]
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References 118 · Cited by 211
- Authors
- Zhang, Q., Duan, J., Liu, X., & Guo, S.-W.
- Affiliations
- Fudan University (CN)
- Shanghai Medical College of Fudan University (CN)
- Corresponding author
- Guo, Sun-Wei
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 428
- Pages
- 1-16
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2299003422
- Cited by
- 211
- References
- 118
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 23 · 2023: 19 · 2022: 23 · 2021: 21 · 2020: 34 · 2019: 15 · 2018: 19 · 2017: 12 · 2016: 10
- FWCI
- 24.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81270676, 81471434, 81530040, 81070470, 81370695)
- Shanghai Municipal Commission of Health and Family Planning (2013ZYJB0019)
- 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 › Urology › Periodontal Regeneration and Treatments
- Keywords
- endometriosis, platelets, fibrogenesis, epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, TGF-β1, TGF-β/Smad signaling, endometriotic stromal cells, collagen synthesis, alpha-smooth muscle actin, cell contractility, wound healing
- MeSH terms
- Actins, Adult, Blood Platelets, Cell Movement, Collagen, Endometriosis, Epithelial Cells, Female, Fibrosis, Humans, Metaplasia, Models, Biological, Muscle, Smooth, Phenotype, Signal Transduction, Platelet Activation, Antigens, CD, Cadherins, Stromal Cells, Cell Shape, Smad3 Protein, Transforming Growth Factor beta1, Cell Transdifferentiation, Myofibroblasts, Epithelial-Mesenchymal Transition
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