Luminal epithelium in endometrial fragments affects their vascularization, growth and morphological development into endometriosis-like lesions

Dilu Feng,Hongbo Wang,Michael D Menger,Matthias W Laschke

doi:10.1242/dmm.013664

Abstract

ABSTRACTIn endometriosis research, endometriosis-like lesions are usually induced in rodents by transplantation of isolated endometrial tissue fragments to ectopic sites. In the present study, we investigated whether this approach is affected by the cellular composition of the grafts. For this purpose, endometrial tissue fragments covered with luminal epithelium (LE+) and without luminal epithelium (LE−) were transplanted from transgenic green-fluorescent-protein-positive (GFP+) donor mice into the dorsal skinfold chamber of GFP− wild-type recipient animals to analyze their vascularization, growth and morphology by means of repetitive intravital fluorescence microscopy, histology and immunohistochemistry during a 14-day observation period. LE− fragments developed into typical endometriosis-like lesions with cyst-like dilated endometrial glands and a well-vascularized endometrial stroma. In contrast, LE+ fragments exhibited a polypoid morphology and a significantly reduced blood perfusion after engraftment, because the luminal epithelium prevented the vascular interconnection with the microvasculature of the surrounding host tissue. This was associated with a markedly decreased growth rate of LE+ lesions compared with LE− lesions. In addition, we found that many GFP+ microvessels grew outside the LE− lesions and developed interconnections to the host microvasculature, indicating that inosculation is an important mechanism in the vascularization process of endometriosis-like lesions. Our findings demonstrate that the luminal epithelium crucially affects the vascularization, growth and morphology of endometriosis-like lesions. Therefore, it is of major importance to standardize the cellular composition of endometrial grafts in order to increase the validity and reliability of pre-clinical rodent studies in endometriosis research.

Highlights

Endometriosis, which is defined as the presence of ectopic endometrial tissue in the form of endometriotic lesions outside the uterine cavity, is one of the most frequent gynecological diseases (Guo and Wang, 2006)
Implications and future directions This study reveals that absence of luminal epithelium of endometrial tissue fragments is crucial for their successful vascularization, growth and morphological development into endometriosis-like lesions in mice
We found that the vascularization, morphology and growth of endometriosis-like lesions originating from LE+ fragments markedly differ from those of LE– fragments

Summary

Introduction

Endometriosis, which is defined as the presence of ectopic endometrial tissue in the form of endometriotic lesions outside the uterine cavity, is one of the most frequent gynecological diseases (Guo and Wang, 2006). There is a substantial need for novel therapeutic strategies that are better tolerated and more efficient than the currently applied pharmacological and surgical approaches. For this purpose, it is necessary to gain better insights into the pathogenesis of endometriosis, which is still sparsely understood. The most widely accepted one, is still Sampson’s theory of retrograde menstruation of endometrial tissue fragments into the peritoneal cavity, where they attach to the peritoneum and develop into vascularized endometriotic lesions (Sampson, 1927)

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Conclusion