Disturbed progesterone signalling in an advanced preclinical model of endometriosis.

Fereshteh Esfandiari, Heidar Heidari Khoei, Maryam Saber, Raha Favaedi, Abbas Piryaei, Ashraf Moini, Maryam Shahhoseini, Fariba Ramezanali, Firouzeh Ghaffari, Hossein Baharvand

Journal: Reproductive biomedicine online 2022;43(1):139-147

PMID: 34049811

Full Text on Elsevier Science View on PubMed

Abstract

RESEARCH QUESTION

Do human endometriosis organoids recapitulate aberrant progesterone signalling in the disease to serve as advanced experimental models for uncovering epigenetic mechanisms involved in attenuated progesterone response in endometriosis?

DESIGN

Initially, the organoids were established from acquired biopsies (women with and without endometriosis) and characterized by morphological, histological and immunostaining analyses.

RESULTS

A panel of endometriosis-related genes showed a pattern of expressions in cytochrome c oxidase subunit II (COX2), matrix metalloproteinase 2 (MMP2), MMP9, tissue inhibitor of metalloproteinase-3 (TIMP3), transforming growth factor beta 1 (TGF-β1), and zinc finger E-box binding homeobox 1 (ZEB1), and a contradictory expression pattern for cadherin (CDH1), POU class 5 homeobox 1 (POU5F1; also known as OCT4), and Nanog homeobox (NANOG) in the endometriosis organoids that is concordant with published research. These endometriosis organoids failed to upregulate 17β-Hydroxysteroid dehydrogenase 2 (17HSDβ2), progestogen associated endometrial protein (PAEP), secreted phosphoprotein 1 (SPP1), and leukaemia inhibitory factor (LIF) in response to progesterone at the level observed in control endometrium organoids. Progesterone receptor B (PRB) gene expression significantly decreased in both eutopic and ectopic organoids compared with control endometrium organoids. DNA hypermethylation, as an epigenetic mechanism for suppression of transcription, was detected at the PRB promoter in the eutopic, but not ectopic, organoids. Therefore, other epigenetic mechanisms, such as histone modifications and microRNAs, may be responsible for PRB downregulation in ectopic organoids.

CONCLUSIONS

Endometriosis organoids are powerful preclinical models that can be used to investigate the molecular mechanisms involved in endometriosis-associated progesterone resistance.

Address: Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Square, Banihashem Street, Resalat Highway, 1665659911, PO Box 16635-148 Tehran, Iran.; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR Tehran, Iran.; Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences Tehran, Iran; Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences Tehran, Iran.; Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR Tehran, Iran; Department of Obstetrics and Gynecology, Arash Women's Hospital, Tehran University of Medical Sciences Tehran, Iran; Breast Disease Research Center (BDRS), Tehran University of Medical Sciences Tehran, Iran.; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR Tehran, Iran; Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR Tehran, Iran; Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran Tehran, Iran.; Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR Tehran, Iran.; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Banihashem Square, Banihashem Street, Resalat Highway, 1665659911, PO Box 16635-148 Tehran, Iran; Department of Developmental Biology, University of Science and Culture Tehran, Iran. Electronic address: [email protected].

DOI: 10.1016/j.rbmo.2020.12.011