Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations

Abstract

Our understanding of the etiology and pathophysiology of endometriosis remains limited. Disease modelling in the field is problematic as many versions of induced mouse models of endometriosis exist. We integrated bioluminescent imaging of ‘lesions’ generated using luciferase-expressing donor mice. We compared longitudinal bioluminescence and histology of lesions, sensory behavior of mice with induced endometriosis and the impact of the GnRH antagonist Cetrorelix on lesion regression and sensory behavior. Four models of endometriosis were tested. We found that the nature of the donor uterine material was a key determinant of how chronic the lesions were as well as their cellular composition. The severity of pain-like behavior also varied across models. Whilst Cetrorelix significantly reduced lesion bioluminescence in all models, it had varying impacts on pain-like behavior. Collectively, our results demonstrate key differences in the progression of the ‘disease’ across different mouse models of endometriosis. We propose that validation and testing in multiple models, each of which may be representative of the different subtypes / heterogeneity observed in women should become a standard approach to discovery science in the field of endometriosis.

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain

“…Another weakness of our model is that the immune system of recipient animals is defective on the lymphoid lineage. So, although monocytes [ 41 ] and mast cells [ 38 ], which play an important n role in endometriosis-related inflammatory pain [ 42 ], are present, their interaction with the adaptive system is not preserved.…”

Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

“…Overall, a progressive decline in lesion size was observed in all model variants, but bioluminescent imaging showed some progression in size and new lesion formation in NI and MI mice. Lesions in DO and DI mice were mostly located on the peritoneal wall and mesentery/fat, while lesions in NI and MI mice were split relatively evenly between the peritoneal wall, mesentery/fat, and other locations like the bladder and wall of the uterus (Dorning et al, 2021).…”

“…Due to the difficulty in reliably locating lesions, particularly for longitudinal analyses, a variety of luminescence strategies (e.g., GFP uterine tissue) have evolved. Dorning et al (2021) compared four variants of the intraperitoneal injection method: decidualized tissue into an ovariectomized, but E2 supplemented, recipient (DO), decidualized tissue into a hormonally intact recipient (DI), minced naïve endometrium from cycling mice into hormonally intact recipients (NI), and full thickness uterine fragments, including the myometrium, from cycling mice into hormonally intact recipients (MI). Lesion progression was longitudinally analyzed at 7, 21, and 42 days by in vivo imaging of luciferase bioluminescence.…”

“…When transgenic mice or tissues expressing firefly luciferase under the ubiquitin C promotor (UbC-Luc) are treated with luciferin, a detectable bioluminescent signal is expressed (Becker et al, 2006). In the context of a mouse model of endometriosis, transplanting uterine tissue from a donor UbC-Luc mouse into a wild-type recipient mouse and injecting luciferin subcutaneously, into the tail vein, or into the peritoneal cavity of the recipient prior to in vivo imaging will result in bioluminescence of lesions (Wang et al, 2013;Dorning et al, 2021). Lesion size and weight can be correlated with signal intensity (Wang et al, 2013;Dorning et al, 2021).…”

“…In the context of a mouse model of endometriosis, transplanting uterine tissue from a donor UbC-Luc mouse into a wild-type recipient mouse and injecting luciferin subcutaneously, into the tail vein, or into the peritoneal cavity of the recipient prior to in vivo imaging will result in bioluminescence of lesions (Wang et al, 2013;Dorning et al, 2021). Lesion size and weight can be correlated with signal intensity (Wang et al, 2013;Dorning et al, 2021). Unfortunately, as with fluorescence, coat color of the mouse strain affects the in vivo detection of luminescence, with black coat reducing luminescence by ∼10 fold (Becker et al, 2006).…”