Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10

Rishi Man Chugh,Dalia Ashour,Prosper Igboeli,Jan Mcallister,Mara Ulin,Lale Bakir,Abdeljabar El Andaloussi,Hang-Soo Park,Sahar Esfandyari,Mohamed Ali,Nahed Ismail,Amro Elsharoud,Alshimaa Aboalsoud,Ayman Al-Hendy

doi:10.1186/s13287-021-02472-w

Abstract

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models.MethodsFor in vitro experiment, we treated conditioned media from BM-hMSC to androgen-producing H293R cells and analyzed androgen-producing gene expression. For in vivo experiment, BM-hMSC were implanted into letrozole (LTZ)-induced PCOS mouse model. BM-hMSC effect in androgen-producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery.ResultsBM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improved in metabolic and reproductive markers in our PCOS model and able to restore fertility.ConclusionOur study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.

Highlights

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women
bone marrow mesenchymal stem cells (BM-hMSC) secretome decreases steroidogenesis-related gene expression and androgen production in H295R cells We previously reported that CYP17A1, CYP11A1, and DENND1A, key genes for ovarian androgen biosynthesis, are upregulated in PCOS-theca cells compared with healthy theca cells [27, 33]
We confirmed these findings at the protein level using immunoblot analysis, which showed that CYP17A1 (0.84 ± 0.02 fold) and DENND1A (0.26 ± 0.01 fold) were significantly decreased in secretome-treated H295R cells compared with the control group, while no change was observed in CYP11A1 (0.97 ± 0.02 fold, p=0.41; Fig. 1c, d)

Summary

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Many women with PCOS exhibit metabolic aberrations such as insulin resistance, dyslipidemia, and hypertension, which are often worsened by concomitant abdominal adiposity or frank obesity These factors can predispose women to abnormal glucose tolerance, cardiovascular disease, and even full-blown metabolic syndrome [5,6,7]. Anti-inflammatory therapy has been shown to reduce ovarian androgen secretion and induce ovulation in lean, insulin-sensitive women with PCOS [14].

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