Abstract
Adenomyosis is related to infertility and miscarriages, but so far there are no robust in vitro models that reproduce its pathological features to study the molecular mechanisms involved in this disease. Endometrial organoids are in vitro 3D models that recapitulate the native microenvironment and reproduce tissue characteristics that would allow the study of adenomyosis pathogenesis and related infertility disorders. In our study, human endometrial biopsies from adenomyosis (n = 6) and healthy women (n = 6) were recruited. Organoids were established and hormonally differentiated to recapitulate midsecretory and gestational endometrial phases. Physiological and pathological characteristics were evaluated by immunohistochemistry, immunofluorescence, qRT-PCR, and ELISA. Secretory and gestational organoids recapitulated in vivo glandular epithelial phenotype (pan-cytokeratin, Muc-1, PAS, Laminin, and Ki67) and secretory and gestational features (α-tubulin, SOX9, SPP1, PAEP, LIF, and 17βHSD2 expression and SPP1 secretion). Adenomyosis organoids showed higher expression of TGF-β2 and SMAD3 and increased gene expression of SPP1, PAEP, LIF, and 17βHSD2 compared with control organoids. Our results demonstrate that organoids derived from endometria of adenomyosis patients and differentiated to secretory and gestational phases recapitulate native endometrial-tissue-specific features and disease-specific traits. Adenomyosis-derived organoids are a promising in vitro preclinical model to study impaired implantation and pregnancy disorders in adenomyosis and enable personalized drug screening.
Highlights
Adenomyosis is a benign uterine disease affecting 35% of women of reproductive age [1], characterized by invagination of endometrial glands and stroma into the myometrium [2]
Other authors support that ectopic lesions could be due to endometrial stem cells (ESCs) that are transported in retrograde menstruation [11,12], which have the ability to adhere, implant, differentiate, and propagate in ectopic locations [13]
Control group is based on young healthy women included in an egg donation (ED) program with a standard uterine volume, with no evidence of adenomyotic lesions by ultrasound, who were free from other gynecologic pathologies and without medication during the previous 3 months, as condition to be included in the ED program
Summary
Adenomyosis is a benign uterine disease affecting 35% of women of reproductive age [1], characterized by invagination of endometrial glands and stroma into the myometrium [2]. The second theory is that adenomyotic lesions are generated de novo rather than originating from the eutopic endometrium [4,5] This would be due to a differentiation of the misplaced Müllerian remnants into tissue that resembles endometrial tissue and would grow in ectopic sites [9,10]. One third of women affected by adenomyosis is asymptomatic, most of them may present abnormal uterine bleeding, chronic pelvic pain, dysmenorrhea, or dyspareunia [19]. This condition can result in infertility and miscarriages [19], leading most affected women to undergo assisted reproductive techniques [20]. Meta-analyses found that implantation, clinical and ongoing pregnancy, and live birth rates are significantly lower in patients with adenomyosis compared with healthy women, while miscarriage rates are higher [21,22,23]
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