Fibromuscular differentiation in deeply infiltrating endometriosis is a reaction of resident fibroblasts to the presence of ectopic endometrium
Abstract
BACKGROUND: In this study, we characterized the fibromuscular (FM) tissue, typical of deeply infiltrating endometriosis, investigated which cells are responsible for the FM reaction and evaluated whether transforming growth factor-beta (TGF-beta) signaling is involved in this process. METHODS: FM differentiation and TGF-beta signaling were assessed in deeply infiltrating endometriosis lesions (n = 20) and a nude mouse model of endometriosis 1, 2, 3 and 4 weeks post-transplantation. The FM reaction was evaluated by immunohistochemistry using different markers of FM and smooth muscle cell differentiation (vimentin, desmin, alpha-smooth muscle actin, smooth muscle myosin heavy chain). TGF-beta signaling was assessed by immunostaining for its receptors and phosphorylated Smad. RESULTS: Deeply infiltrating endometriosis lesions contain myofibroblast-like cells that express multiple markers of FM differentiation. Expression of TGF-beta receptors and phospho-Smad was more pronounced in the endometrial component of the lesions than in the FM component. In the nude mouse model, alpha-smooth muscle actin expression was observed in murine fibroblasts surrounding the lesion, but not in human endometrial stroma. CONCLUSIONS: FM differentiation in deeply infiltrating endometriosis is the result of a reaction of the local environment to the presence of ectopic endometrium. It shares characteristics with pathological wound healing, but cannot be explained by TGF-beta signaling alone.
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DE is characterized by the presence of smooth muscle metaplasia (SMM) and a high degree of fibrotic tissues.
“One feature that DE stands out from other subtypes of endometriosis is its presence of smooth muscle metaplasia (SMM) and its high degree of fibrotic tissues4,15–17”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [17]
DE lesions typically have higher fibromuscular content than ovarian endometriomas (OE) lesions.
“DE lesions typically have higher fibromuscular content than that of ovarian endometriomas (OE) lesions, but the underlying reason remains elusive.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [17]
The findings explain why DE lesions have abundant SMC-like cells and more extensive fibrosis than OE lesions.
“This also provides an answer to a long-standing conundrum as why DE lesions have abundant SMC-like cells17,25,46 and more extensive fibrosis than that of OE lesions2,4,24,28,46.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [17]
The fibromuscular tissue in deep endometriosis shares characteristics with pathological wound healing, although the process could not be explained by TGF-b alone.
“Van Kaam et al. (47) characterized the fibromuscular tissue and showed that the tissue shared characteristics with pathological wound healing, although the process could not be explained by transforming growth factor-b (TGF-b) alone.”
From Pathogenesis of deep endometriosis (2017) · cites this paper as [47]
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- Authors
- van Kaam, K. J. A. F., Schouten, J. P., Nap, A. W., Dunselman, G. A. J., & Groothuis, P. G.
- Affiliations
- Maastricht University Medical Centre (NL)
- Organon (Netherlands) (NL)
- Venue
- Human Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-01
- Volume
- 23
- Issue
- 12
- Pages
- 2692-2700
- ISSN
- 0268-1161 (ISSN-L)
- 1460-2350
- OpenAlex
- W2158463125
- Cited by
- 70
- References
- 41
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 8 · 2015: 3 · 2014: 8 · 2013: 1 · 2012: 5
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Reproduction (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ectopic Pregnancy Diagnosis and Management
- Keywords
- deep infiltrating endometriosis, myofibroblasts, TGF-beta signaling, TGF-beta receptor, Smad phosphorylation, ectopic endometrium, smooth muscle differentiation, alpha-smooth muscle actin
- MeSH terms
- Animals, Cell Differentiation, Choristoma, Endometriosis, Female, Fibroblasts, Humans, Mice, Nude, Muscle, Smooth, Signal Transduction, Transforming Growth Factor beta, Receptors, Transforming Growth Factor beta, Mice, Smad2 Protein, Transforming Growth Factor beta1, Transforming Growth Factor beta2
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