Cellular Changes Consistent With Epithelial–Mesenchymal Transition and Fibroblast-to-Myofibroblast Transdifferentiation in the Progression of Experimental Endometriosis in Baboons

Zhang Q, Qi Zhang, Jie Duan, Duan J, Mark Olson, Olson M, Asgerally Fazleabas, Asgerally T Fazleabas, Fazleabas A, Sun-Wei Guo, Sun‐Wei Guo, Guo SW
Reproductive sciences (Thousand Oaks, Calif.) · 2016 · vol. 23(10) , pp. 1409–1421 · doi:10.1177/1933719116641763 · PMID:27076446 · PMC5933178 · W2340786628
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This study found that progressive epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation, driven by TGF-β1/Smad3 activation and platelets, lead to fibrosis in baboon endometriosis lesions.

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This paper investigated the progression of induced endometriosis in baboons by testing whether lesion development involves platelet-driven epithelial–mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), mediated by TGF-β1/Smad3 signaling, leading to smooth muscle metaplasia and fibrosis. Using serially dissected endometriotic tissue samples, the authors performed immunohistochemistry and immunofluorescence analyses and found increasing vimentin in epithelial compartments, apparent increases in smooth muscle cells with lesion time, elevated TGF-β1 and phosphorylated Smad3, and increases in α-smooth muscle actin-positive myofibroblasts and highly differentiated smooth muscle cells that correlated with greater fibrosis. A major limitation is that the work is based on tissue marker patterns over time in an experimental model rather than direct causal manipulation within each lesion stage. This paper is centrally about endometriosis — it characterizes EMT/FMT progression and TGF-β1/Smad3-associated fibrogenesis in experimentally induced endometriosis in baboons.

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Abstract

We have recently shown that platelets play important roles in development of endometriosis and proposed that endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair (ReTIAR). Further investigation indicated that endometriotic lesions, stimulated by platelet-derived transforming growth factor β1 (TGF-β1), activate the TGF-β1/Smad3 signaling pathway and undergo epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), resulting in increased cellular contractility and collagen production and increased smooth muscle metaplasia (SMM), leading to fibrosis. Using serially dissected endometriotic tissue samples from baboons with induced endometriosis, we tested the hypothesis of progressive EMT, FMT, SMM, and fibrosis through TGF-β1/Smad activation using immunohistochemistry and immunoflurescence staining analyses. We found that platelets are aggregated in endometriotic lesions, and vimentin expression was increased in the epithelial compartment of the lesions as they progressively developed. We also found that the number of smooth muscle cells (SMCs) appeared to increase with time as lesions progressed and was concomitant with the increased vimentin-positive glandular epithelial cells in the lesions. As lesion development progressed, TGF-β1 and phosphorylated-Smad3 staining was elevated and the number of α-smooth muscle actin-positive myofibroblasts and highly differentiated SMCs increased in the stromal compartment, which correlated with the increasing extent of fibrosis. These results, taken together, provide support for the notion that ReTIAR occurs in the endometriotic lesions, resulting in EMT and FMT, leading to SMM and ultimately fibrosis as lesions progress. Consequently, our data also provide corroborative evidence that platelets drive the EMT and FMT in endometriotic lesions over time, promoting SMM and resulting ultimately in fibrosis in the endometriotic lesions. These findings cast a new light on the natural history of endometriosis which so far has been elusive.
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Abstract

We have recently shown that platelets play important roles in development of endometriosis and proposed that endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair (ReTIAR). Further investigation indicated that endometriotic lesions, stimulated by platelet-derived transforming growth factor β1 (TGF-β1), activate the TGF-β1/Smad3 signaling pathway and undergo epithelial–mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), resulting in increased cellular contractility and collagen production and increased smooth muscle metaplasia (SMM), leading to fibrosis. Using serially dissected endometriotic tissue samples from baboons with induced endometriosis, we tested the hypothesis of progressive EMT, FMT, SMM, and fibrosis through TGF-β1/Smad activation using immunohistochemistry and immunoflurescence staining analyses. We found that platelets are aggregated in endometriotic lesions, and vimentin expression was increased in the epithelial compartment of the lesions as they progressively developed. We also found that the number of smooth muscle cells (SMCs) appeared to increase with time as lesions progressed and was concomitant with the increased vimentin-positive glandular epithelial cells in the lesions. As lesion development progressed, TGF-β1 and phosphorylated-Smad3 staining was elevated and the number of a-smooth muscle actin-positive myofibroblasts and highly differentiated SMCs increased in the stromal compartment, which correlated with the increasing extent of fibrosis. These results, taken together, provide support for the notion that ReTIAR occurs in the endometriotic lesions, resulting in EMT and FMT, leading to SMM and ultimately fibrosis as lesions progress. Consequently, our data also provide corroborative evidence that platelets drive the EMT and FMT in endometriotic lesions over time, promoting SMM and resulting ultimately in fibrosis in the endometriotic lesions. These findings cast a new light on the natural history of endometriosis which so far has been elusive. Similar content being viewed by others

References

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D’Hooghe, TM, Bambra, CS, Raeymaekers, BM, Koninckx, PR Development of spontaneous endometriosis in baboons. Obstet Gynecol. 1996;88(3):462–466. Koninckx, PR, Ussia, A, Adamyan, L, Wattiez, A An endome-triosis classification, designed to be validated. Gynecol Surg. 2011;8(1):1–6. Zhang, Q, Duan, J, Liu, X, Guo, SW Platelets drive smooth muscle metaplasia and fibrogenesis in endometriosis through epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation. Mol Cell Endocrinol, 2016;428:1–16. Author information Authors and Affiliations Corresponding authors Rights and permissions About this article Cite this article Zhang, Q., Duan, J., Olson, M. et al. Cellular Changes Consistent With Epithelial–Mesenchymal Transition and Fibroblast-to-Myofibroblast Transdifferentiation in the Progression of Experimental Endometriosis in Baboons. Reprod. Sci. 23, 1409–1421 (2016). https://doi.org/10.1177/1933719116641763 Published: Issue date: DOI: https://doi.org/10.1177/1933719116641763

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endometriosis

MeSH descriptors

Cell Transdifferentiation Disease Progression Endometriosis Endometriosis Epithelial-Mesenchymal Transition Fibroblasts Myofibroblasts Animals Disease Models, Animal Endometriosis Endometriosis Epithelial Cells Epithelial Cells Female Fibroblasts Fibrosis Metaplasia Muscle, Smooth Muscle, Smooth Myofibroblasts

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