Zhang Qi, Duan Jie, Olson Mark, Fazleabas Asgerally, Guo Sun-Wei
Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA.
Reprod Sci. 2016 Oct;23(10):1409-21. doi: 10.1177/1933719116641763. Epub 2016 Apr 12.
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.
我们最近发现血小板在子宫内膜异位症的发展中起重要作用，并提出子宫内膜异位症病变本质上是经历反复组织损伤和修复（ReTIAR）的伤口。进一步研究表明，受血小板衍生的转化生长因子β1（TGF-β1）刺激的子宫内膜异位症病变会激活TGF-β1/Smad3信号通路，并经历上皮-间质转化（EMT）和成纤维细胞向肌成纤维细胞的转分化（FMT），导致细胞收缩性和胶原蛋白生成增加以及平滑肌化生（SMM）增加，从而导致纤维化。我们使用从患有诱导性子宫内膜异位症的狒狒身上连续解剖的子宫内膜异位症组织样本，通过免疫组织化学和免疫荧光染色分析，检验了通过TGF-β1/Smad激活实现渐进性EMT、FMT、SMM和纤维化的假设。我们发现血小板聚集在子宫内膜异位症病变中，并且随着病变的逐渐发展，波形蛋白表达在病变的上皮区域增加。我们还发现，随着病变进展，平滑肌细胞（SMC）的数量似乎随时间增加，并且与病变中波形蛋白阳性腺上皮细胞的增加相伴。随着病变发展的推进，TGF-β1和磷酸化Smad3染色升高，并且α-平滑肌肌动蛋白阳性肌成纤维细胞和高度分化的SMC数量在间质区域增加，这与纤维化程度的增加相关。综上所述，这些结果支持了ReTIAR发生在子宫内膜异位症病变中，导致EMT和FMT，随着病变进展导致SMM并最终导致纤维化的观点。因此，我们的数据还提供了确证性证据，即随着时间的推移，血小板驱动子宫内膜异位症病变中的EMT和FMT，促进SMM并最终导致子宫内膜异位症病变中的纤维化。这些发现为迄今为止一直难以捉摸的子宫内膜异位症的自然病史提供了新的线索。
