Mesenchymal Stem Cell Therapy Ameliorates Metabolic Dysfunction and Restores Fertility in a PCOS Mouse Model Through Interleukin-10

Abstract

Background: Polycystic 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.Methods: For 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 mouse PCOS 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.Results: BM-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 improve in metabolic and reproductive markers in our PCOS model and able to restore fertility. Conclusion: Our 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.

Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels

“…Providing evidence of a role for altered cytokine levels in the observed normalisation of corticosterone fluctuations in SGLT2 null mice, treatment of adrenal gland cells with IL-6 upregulated CYP11A1 and HSD3B2, in line with previous findings (39). An upward trend was also observed following treatment with leptin (40) and IL-1β (41), while IL-10 and TGFβ1 had no effect, again mirroring earlier results (42,43). Interestingly, FGF21 appeared to cause a slight increase in the expression of the two enzymes, an effect previously described in rodents as a part of a glucocorticoid to FGF21 feed-forward loop (44).…”

Stem cells and exosomes: as biological agents in the diagnosis and treatment of polycystic ovary syndrome (PCOS)

“…Interleukin-10 (IL-10) was discovered to be a key mediator of the therapeutic benefits of BM-MSC treatment in PCOS animals. The reported results indicate that BM-hMSC therapy effectively improves fertility and positively impacts metabolic and reproductive parameters in PCOS animal models (4).…”

“…Recent studies have shown that in lean, insulin-sensitive women with PCOS, the use of anti-inflammatory medication can reduce ovarian androgen release and promote ovulation. Interestingly, even in cases where insulin resistance is absent in PCOS, the data clearly indicate that inflammation acts as a crucial character in the underlying mechanism behind ovarian dysfunction (4,5).…”

Androgen excess: a hallmark of polycystic ovary syndrome

“…After the injection of human bone marrow MSCs into the ovary, androgensynthesizing gene expression, including CYP17A1 and DENND1A, was significantly downregulated, while FSHR and CYP19A1 gene expression was upregulated. These effects were partly mediated by secretome components IL-10 and BMP-2 (143,144). One study further uncovered several key protein components from hMSCs regulating androgen production (145).…”