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Mimicking Sampson's Retrograde Menstrual Theory in Rats: A New Rat Model for Ongoing Endometriosis-Associated Pain.

ABSTRACT: Endometriosis is a prevalent gynecologic disease, defined by dysfunctional endometrium-like lesions outside of the uterine cavity. These lesions are presumably established via retrograde menstruation, i.e., endometrial tissue that flows backwards during menses into the abdomen and deposits on the organs. As ongoing pain is one of the main pain symptoms of patients, an animal model that illuminates this problem is highly anticipated. In the present study, we developed and validated a rat model for ongoing endometriosis-associated pain. First, menstrual endometrial tissue was successfully generated in donor rats, as validated by gross examination, histology and qPCR. Next, endometriosis was induced in recipient animals by intraperitoneal injection of menstrual tissue. This resulted in neuro-angiogenesis as well as established endometriosis lesions, which were similar to their human counterparts, since epithelial and stromal cells were observed. Furthermore, significant differences were noted between control and endometriosis animals concerning bodyweight and posture changes, indicating the presence of ongoing pain in animals with endometriosis. In summary, a rat model for endometriosis was established that reliably mimics the human pathophysiology of endometriosis and in which signs of ongoing pain were detected, thus providing a new research tool for therapy development.

SUBMITTER: Persoons E

PROVIDER: S-EPMC7177935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Endometriosis is a chronic and underdiagnosed disease which affects 5-10% of women of childbearing age and is characterized by growth of endometrial tissue outside of the uterus, most often in the peritoneal cavity. Delay in diagnosis is a major problem for management of this disorder, and treatment is often not initiated until the disease has progressed for many years. Although the exact etiology of endometriosis remains unknown, retrograde menstruation is recognized as a common underlying factor leading to the deposit of menstrual effluent (ME) into the peritoneal cavity. Differences in the cellular biology and genetics of the cells within ME are therefore likely to explain why endometriosis develops in only a subset of women.Patients with and without endometriosis were consented to provide ME. ME was analyzed by flow cytometry for CD45- and CD45+ cell populations or used to isolate stromal fibroblast cells. ME-derived stromal fibroblast cells were assessed using decidualization assays following the addition of cAMP and IGFBP-1 concentrations in the culture supernatants were measured by ELISA. In addition, RNA was collected and analyzed by RNA-Seq and qPCR for markers of decidualization and to identify differentially expressed genes in ME-derived stromal fibroblast cells obtained from controls and subjects with endometriosis (±cAMP).Flow cytometry analysis of cell subsets within the CD45+ fraction of ME revealed a significant decrease in the number of uterine NK cells in endometriosis patients compared with controls (p?<?0.01). No other significant differences within either the CD45+ or CD45- cell populations were observed. Most strikingly, ME-derived stromal fibroblast cells cultured from endometriosis subjects showed impaired decidualization potential compared with controls. Highly significant differences in decidualization response were detected by measuring IGFBP-1 production at multiple time points after cAMP stimulation (p?=?0.0025 at 6 h; p?=?0.0045 at 24 h; p?=?0.0125 at 48 h). RNA-Seq and qPCR analyses were used to identify genes differentially expressed by ME-derived stromal fibroblast cells obtained from endometriosis and control subjects.Menstrual effluent can be useful for investigating the pathobiology of endometriosis and for developing a non-invasive diagnostic for endometriosis which may lead to earlier and more effective treatments for this common disorder.

Project description:Pain is the most severe and common symptom of endometriosis. Its underlying pathogenetic mechanism is poorly understood. Nerve sensitization is a particular research challenge, due to the limitations of general endometriosis models and sampling nerve tissue from patients. The chemokine fractalkine (FKN) has been demonstrated to play a key role in various forms of neuropathic pain, while its role in endometriotic pain is unknown. Our study was designed to explore the function of FKN in the development and maintenance of peripheral hyperalgesia and central sensitization in endometriosis using a novel endometriosis animal model developed in our laboratory. After modeling, behavioral tests were carried out and the optimal time for molecular changes was obtained. We extracted ectopic tissues and L4-6 spinal cords to detect peripheral and central roles for FKN, respectively. To assess morphologic characteristics of endometriosis-like lesions-as well as expression and location of FKN/CX3CR1-we performed H&E staining, immunostaining, and western blotting analyses. Furthermore, inhibition of FKN expression in the spinal cord was achieved by intrathecal administration of an FKN-neutralizing antibody to demonstrate its function. Our results showed that implanted autologous uterine tissue around the sciatic nerve induced endometriosis-like lesions and produced mechanical hyperalgesia and allodynia. FKN was highly expressed on macrophages, whereas its receptor CX3CR1 was overexpressed in the myelin sheath of sciatic nerve fibers. Overexpressed FKN was also observed in neurons. CX3CR1/pp38-MAPK was upregulated in activated microglia in the spinal dorsal horn. Intrathecal administration of FKN-neutralizing antibody not only reversed the established mechanical hyperalgesia and allodynia, but also inhibited the expression of CX3CR1/pp38-MAPK in activated microglia, which was essential for the persistence of central sensitization. We concluded that the FKN/CX3CR1 signaling pathway might be one of the mechanisms of peripheral hyperalgesia in endometriosis, which requires further studies. Spinal FKN is important for the development and maintenance of central sensitization in endometriosis, and it may further serve as a novel therapeutic target to relieve persistent pain associated with endometriosis.

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Mimicking Sampson's Retrograde Menstrual Theory in Rats: A New Rat Model for Ongoing Endometriosis-Associated Pain.

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