Myofibroblasts Are Evidence of Chronic Tissue Microtrauma at the Endometrial-Myometrial Junctional Zone in Uteri With Adenomyosis

Ibrahim, M. G.; Sillem, Martin; Plendl, Johanna; Chiàntera, Vito; Sehouli, Jalid; Mechsner, Sylvia

doi:10.1177/1933719116687855

Cited by 43 publications

(42 citation statements)

References 33 publications

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“…The key factor is the local (peritoneal) environment that induces the different types of endometriosis. That E receptors (ERs) and PRs are present not only in glands and stroma but also in the smooth muscle component of deep endometriosis (229), and the expression of a-smooth muscle actin and collagen I in and around endometriotic lesions support the notion of the metaplastic process (230).…”

Section: Discussionmentioning

confidence: 90%

Pathogenesis of deep endometriosis

Gordts

Koninckx²,

Brosens

2017

Fertility and Sterility

187

115

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Section: Discussionmentioning

confidence: 90%

Pathogenesis of deep endometriosis

Gordts

Koninckx²,

Brosens

2017

Fertility and Sterility

187

115

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“…However, this common problem has been often overlooked in LM and MM cell cultures because cell types are usually assessed in whole cell lysates, in which SMC markers can be detected even when SMCs are a minor population (33,34). In addition, ACTA2, the most commonly used SMC marker, cannot accurately detect the disappearance of SMCs from cell cultures, as ACTA2 can be induced in non-SMCs of the human uterus (35–39). Given the high initial concentration of TAFs with superior in vitro growth potential, freshly prepared primary cultures of MED12-LMs would contain more fibroblasts than SMCs, and the concentration of SMCs should further decrease, as TAFs grow faster to reach confluence.…”

Section: Discussionmentioning

confidence: 99%

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Wu¹,

Serna²,

Thomas³

et al. 2017

Cancer Research

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Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here we report the elucidation of the biological characteristics of the two most prevalent LM subtypes, MED12 mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) LM. Since each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-LM were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of ECM in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both LM subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these LM subtypes emphasize the importance of subtypes and genotypes in designing non-surgical therapeutic strategies for LM.

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“…Myofibroblasts were involved in the cyclic menstrual injury and scarless regeneration through wound contraction and synthesis and remodeling of ECM (Maybin and Critchley 2015). Excessive activation of myofibroblasts caused by abnormal regulations were highly correlated with adenomyosis (Ibrahim et al 2017) and endmetriosis (van Kaam et al 2008) through abnormal deposition of extracellular matrix from myofibroblast, the discovery of its dysregulation factors may shed light on the pathogenesis of these diseases (Liu et al 2016).…”

Section: Heterogeneity Of Uterus Smooth Muscle and Myofibroblastsmentioning

confidence: 99%

Cell atlas of human uterus

Liu

et al. 2018

Preprint

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The human uterus is a highly dynamic tissue that undergoes repeated damage repair and regeneration during the menstrual cycle, which make it ideal model to study tissue regeneration and pathological process. Stem/progenitors were speculated to be involved in the regeneration of endometrial epithelial and pathogenesis of endometriosis. But the identity, microenvironment and regulatory mechanisms of the uterus epithelial stem/progenitors in vivo remain unclear. Here, we dissected the cell heterogeneities of the full-thickness human uterus epithelial cells (11 clusters), stroma cells (6 clusters), endothelial cells (5 clusters), smooth muscle cells (2 clusters), myofibroblasts (2 clusters) and immune cells (6 clusters) from 2735 single cell by single cell RNA-seq. Further analysis identified a unique ciliated epithelial cell cluster showing characteristics of stem/progenitors with properties of epithelial-mesenchymal transition (EMT) that mainly localized in the upper functionalis of the endometrium. Ordering the cell subpopulations along the pseudo-space revealed cell clusters possess cellular states of stress, inflammation and apoptosis in the upper functionalis cellular ecosystem of the endometrium. Connectivity map between the human uterus subpopulations revealed potential inflammatory (cytokines and chemokines) and developmental (WNT, FGF, VEGF) signals within the upper functionalis cellular ecosystem of the endometrium, especially from other epithelial clusters, regulating cell plasticity of the EMT-epithelial clusters. This study reconstructed the heterogeneities, space-specific distribution and connectivity map of human uterus atlas, which would provide insight in the regeneration of uterus endometria and reference for the pathogenesis of uterus.

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Myofibroblasts Are Evidence of Chronic Tissue Microtrauma at the Endometrial-Myometrial Junctional Zone in Uteri With Adenomyosis

Abstract: The abundant and persistent myofibroblasts (expressing ASMA/collagen I) at EMJZ in AM uteri are ultra-/microscopic evidence of chronic tissue trauma. They are of nonmyometrial origin, as they lack desmin immunolabeling.

Cited by 43 publications

References 33 publications

Pathogenesis of deep endometriosis

Pathogenesis of deep endometriosis

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Cell atlas of human uterus

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