Animal Model of Endometriosis

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1		Hicham Wahnou	--	1282	2023-09-05 21:46:53

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Summary

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Modification

Content Size

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Hicham Wahnou

1282

2023-09-05 21:46:53

1. Contexte

Endometriosis is a prevalent gynecological condition characterized by the abnormal growth and survival of endometrial tissue outside the uterus, resulting in the formation of lesions that vary in size and appearance. These lesions contain endometrial glands and stroma and can lead to symptoms such as pelvic pain and infertility in affected individuals. It is estimated to affect approximately 10% of women in their reproductive years ^[1]. Despite being recognized for over a century, the exact causes and mechanisms behind endometriosis remain poorly understood.

One widely accepted theory, proposed by Sampson in 1927 ^[2], suggests that endometriotic lesions arise from the attachment and growth of endometrial fragments that travel into the peritoneal cavity through retrograde menstruation. However, since retrograde menstruation occurs in nearly all women of reproductive age, additional factors must contribute to the establishment and survival of ectopic endometrial tissue ^[2]. The complexity of endometriosis pathophysiology is compounded by the fact that it is often diagnosed at later stages, making it challenging to study the disease's early development. Ethical constraints also limit controlled experiments in large populations, which could help establish causal relationships and identify specific markers for endometriosis.

To address these limitations, researchers have developed various animal models that simulate endometriosis-like lesions. These models, although not perfect replicas of the human disease, have proven valuable for conducting controlled studies aimed at understanding the mechanisms of endometrial cell attachment, invasion, and persistence at ectopic sites. Two commonly used animal models for endometriosis research involving inbred mouse strains. These models offer unique strengths and limitations and are crucial for investigating the many scientific questions surrounding this complex condition.

2. Mice models

Laboratory mice have become popular choices for endometriosis research due to several advantages. These include their cost-effectiveness, the ability to introduce endometrial tissue into recipient mice, conducting various analyses in genetically similar animals, and studying endometrial lesions over different timeframes to assess the impact of various drugs or treatments ^[3]. However, despite their frequent use in studying endometriosis, mouse models come with notable limitations.

One critical physiological difference between mice and humans is the absence of menstruation in mice, leading to a lack of spontaneous endometriosis development. Consequently, endometriotic lesions in mouse models must be induced either through surgical procedures ^[4] or by injecting endometrial tissue into the peritoneal cavity ^[5]^[6]. Depending on the origin of the tissue used for induction, murine models of endometriosis are categorized into two types: homologous and heterologous models.

2.1. Surgical transplantation

In these models, both donor and recipient animals undergo ovariectomy and receive exogenous estrogen treatment (at a dose of 100 µg/kg intramuscularly). This estrogen treatment is administered to synchronize the estrous cycle and enhance the growth and proliferation of endometrial cells in donor mice, making the obtained endometrial tissue suitable for inducing endometriosis. However, it's important to note that supplementing estrogen in the recipients is likely to influence the development and progression of endometriosis, as estrogen is known to play a role in the pathophysiology of the disease. Despite this limitation, homologous models can still be useful for studying the effects of steroid hormones on ectopic lesions ^[7]^[8]. In these models, uterine tissue responds to steroid hormones similarly to human ectopic endometrial tissue, allowing for the study of hormone effects in a manner that mirrors the hormone dependence observed in human cases. One significant challenge encountered in mouse models is that endometrial lesions tend to be small and embedded within the murine tissue, making them difficult to identify. To address this issue, researchers have developed "fluorescent murine models." In these models, endometrial lesions are more easily distinguishable through the use of transgenic donor mouse strains expressing either the green fluorescent protein (GFP) as seen in the work by Hirata et al. (2005) ^[4] or luciferase, as introduced by Becker et al. (2006) ^[3].

In the first study utilizing GFP, researchers assessed lesion establishment, location, and size by illuminating the peritoneal cavity with a GFP-lighting system two weeks after injection. This approach enabled them to acquire representative images for computer-based quantitative analysis, and they observed that the fluorescence was significantly higher in estrogen-supplemented recipients, aligning with the estrogen-dependence of endometrial lesions ^[4].

In the second model, donor mice were made bioluminescent due to the expression of a luciferase transgene. This "fluorescent" approach allowed researchers to monitor the growth of endometrial ectopic lesions without the need to sacrifice the recipient animals. In their study, they imaged the mice and quantified the bioluminescence of each surgically induced luminescent lesion ^[3].

These fluorescent murine models offer a valuable advantage in tracking endometrial ectopic lesion development and progression, improving our ability to study the disease's characteristics and the effects of various treatments.

2.2.Xenotransplantation

Heterologous murine models are based on the transplantation of human endometrial tissue into immunodeficient mice, achieved through various methods such as inoculation into the peritoneal cavity ^[5], minilaparotomy ^[9], or subcutaneous administration ^[10]. These models aim to compensate for the substantial physiological differences between mouse and human endometrial tissues. Human endometrial tissue for these models can be sourced from menstrual fluid, biopsies at different menstrual cycle stages ^[11], and even ovarian endometriomas ^[10].

For instance, Nisolle et al. (2000) ^[9] investigated the behavior of transplanted human menstrual endometrium into the peritoneal cavity over various time intervals. They reported increased proliferative activity in glandular cells and higher expression of vascular endothelial growth factor (VEGF), indicating the involvement of stromal cells in the attachment process and glandular cells in lesion growth. Similarly, Wang et al. (2005) ^[12] transplanted human endometrial tissue from the late secretory phase into nude mice via laparotomy. They observed fusion between ectopic endometrium and murine tissue, followed by the establishment of a robust blood supply. More recently, researchers have used CBR-luciferase-transformed human endometrial cells to non-invasively and quantitatively assess the establishment and growth of heterologous endometrial tissue in immune-deficient mice, resembling the approach in fluorescent homologous models ^[13].

Heterologous models offer both advantages and disadvantages. On the positive side, they are cost-effective and typically exhibit reduced immunological responses. This is attributed to diminished natural killer (NK) activity and lower numbers of functional T and B cells, lowering the risk of graft vs. host disease and allowing the preservation of implanted human tissue ^[14]^[15]. However, these features render the mice more susceptible to murine pathogens, reducing their lifespan. Furthermore, the mice fail to replicate the immune changes seen at the endometriosis implantation site in humans ^[14]^[16].

3.Limitations

A notable limitation of heterologous models is that transplanted human tissue has a limited lifespan, with human endometrium inoculated in nude mice typically persisting for no longer than 4 weeks ^[17]. Nevertheless, their primary potential lies in the use of human endometrium, enabling the testing of different drugs with potential applications in subsequent clinical trials. Additionally, the mouse-human system allows for the differentiation and independent study of host and donor genes. For example, the use of species-restricted monoclonal antibodies enables the distinction of molecules of donor and recipient origin that may contribute to disease mechanisms. Recent advancements in gene array technologies have further allowed the study of transcripts in both human ^[18] and mouse endometrium (Umezawa et al., 2009), leading to the identification of highly expressed endometrial genes that can serve as tissue-specific markers for this condition.

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