Metformin as a potential agent for modulating the faulty endometriotic mesenchymal stem cells: A case-control study

Mashayekhi P, Parisa Mashayekhi, Mehrdad Noruzinia, Khodaverdi S, Sepideh Khodaverdi
International journal of reproductive biomedicine · 2022 · vol. 20(10) , pp. 861–872 · doi:10.18502/ijrm.v20i10.12270 · PMID:36381355 · PMC9644643 · W4308318369
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-12 ⓘ

Metformin treatment modulated stemness-related gene and microRNA expression in endometriotic endometrial mesenchymal stem cells, potentially restoring self-renewal/differentiation balance.

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This case-control study investigated whether metformin modulates “endometriotic mesenchymal stem cells” (enMSCs) derived from human endometrium, comparing cells from stage III–IV endometriosis patients (n=3) with cells from fertile controls (n=3) using enzymatic isolation, stromal culture, and marker verification by flow cytometry. After 72 hours of metformin exposure (0.1, 1, or 10 mM), metformin did not substantially reduce cell viability (>80%) and was assessed for effects on stemness-related transcripts (OCT4A/OCT4B/OCT4B1, SOX2, NANOG) and miRNAs (miR-200b, let-7b, miR-145) using qPCR, with adipogenic and osteogenic differentiation staining also performed. The paper reports that metformin reduced OCT4 transcripts in enMSCs, showed dose-dependent changes in SOX2 and NANOG, and altered miR-200b expression, with some findings described as “corrective” toward baseline levels in untreated normal enMSCs; however, the study is limited by the small sample size and in vitro outcomes without direct mechanistic pathway testing. This paper is centrally about endometriosis — it specifically examines metformin’s effects on endometriotic mesenchymal stem cells and stemness regulators.

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Abstract

BACKGROUND: According to stem cell theory, it seems that the proliferation/differentiation imbalance in endometrial mesenchymal stem cells (enMSCs) is the leading cause of endometriosis, so targeting them to modulate stemness-relevant factors seems to be a wise choice for endometriosis treatment. OBJECTIVE: We aimed to investigate the effects of metformin on stemness properties of enMSCs by evaluating the expression profile of stemness-related genes and microRNAs (miRNAs). MATERIALS AND METHODS: In this case-control study, MSCs were isolated from the eutopic endometrium of 3 endometriotic and 3 healthy women. After their characterization and culture, they were treated with 0.1, 1, and 10 mM metformin for 72 hr. Finally, the expression of octamer-binding transcription factor (OCT) 4A, OCT4B, OCT4B1, sex determining region Y-Box transcription factor 2, nanog homeobox, microRNA-200b, microRNA-145, and lethal-7b were analyzed by quantitative reverse transcription-polymerase chain reaction. RESULTS: Metformin modulated the expression of stemness-related genes and miRNAs, OCT4A, OCT4B, OCT4B1, sex determining region Y-Box transcription factor 2, nanog homeobox, microRNA-200b, microRNA-145, and lethal-7b in enMSCs, especially at 1 and 10 mM concentration. Notably, metformin had a paradoxical effect on normal enMSCs. CONCLUSION: We showed that metformin could modulate the expression of deregulated genes and miRNAs in faulty enMSCs, and restore their skewed self-renewal/differentiation balance, so it might be a promising drug for endometriosis treatment. The paradoxical effect of metformin on enMSCs and normal enMSCs might be because of their different metabolic patterns, so it requires further investigation to illustrate.
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Section

In the current study, we showed that metformin could modulate the expression of deregulated genes and miRNAs in enMSCs, and may correct their skewed self-renewal/differentiation balance. It might be a promising drug for endometriosis treatment. Furthermore, the hypothesis of different metabolic patterns in normal MSCs and enMSCs could provide a clear explanation for different characteristics of enMSCs and their paradoxical response to metformin compared to normal MSCs. Our results are an important source of information about the in vitro effect of metformin on enMSCs.

Coi Statement

The authors declare that there is no conflict of interest.

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endometriosis

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