Human mesenchymal stem cell therapy of polycystic ovary syndrome (PCOS) enhances adiponectin expression in the fat and protect against brown fat whitening

PCOS is associated with low level of serum adiponectin and brown fat whitening. Exogenous adiponectin treatment of PCOS mice decreases circulating androgen and glucose levels, and reduce body mass. Recently, the key role of ovarian chronic inflammation in pathogenesis of PCOS is more realized. This inflammation leads to induction of androgen production by theca cells which in turn causes the metabolic and reproductive aberrations of PCOS. The utility of human mesenchymal stem cells (hMSCs) as a potential therapy for PCOS is yet to be verified. Additionally, no previous studies have evaluated associations between adiponectin and brown fat activation in PCOS. Preclinical study of PCOS treatment with hMSC. The PCOS animal model was developed in presexual (3 weeks old) C57BL6 female mice by implanting letrozole (LTZ) pellet subcutaneously in the neck area (5 mg/pellet, 90 days release). The control group received placebo pellet. Our study was composed of three groups: 1- Placebo control, 2- LTZ and 3- LTZ treated with hMSCs. Human bone marrow MSCs were collected from a healthy female donor by flow cytometry using standard surface markers. After 5 weeks of LTZ treatment, hMSCs (25x104 cell per ovary) were injected into the ovaries using limited laparotomy. The control mice received sham surgery and were injected with PBS. In this study, we investigated the impact of hMSC implanted into ovaries on adiponectin expression level in white and brown fat, and fat homeostasis in PCOS induced by LTZ. Statistical analysis was done using paired t-test. Values were considered statistically significant when P was less than 0.05 (p<0.05). The Hematoxylin and eosin stain data of brown fat was marked by the store of lipid droplets in LTZ group compared to LTZ treated with hMSC group due to metabolic rearrangement and significant decrease in the energy expenditure rescued by hMSC. This data was supported by PD-L1 and UCP-1 BAT immunohistochemistry staining. Our results also show that LTZ exposure alters brown adipose tissue (BAT) gene expression PGC-1α, UCP-1 and Cidea-1, including adiponectin. However, the treatment with hMSC induces significantly the expression level of adiponectin mRNA in the white gonadal fat (0.046 ± 0.0002) compared to the matched control (0.0035 ± 0.0003) and in the BAT (treated group: 3.2 ± 1.3; control: 0.452057 ± 0) (P < 0.005). In addition, leptin mRNA expression was significantly induced in BAT by LTZ (0.071452 ± 0.005) compared to treated group with hMSC (0.011 ± 0.001) (P < 0.05). In addition, hMSC-adiponectin induced was able to regulate the plasticity of resident beige fat cells in gonadal white fat, into brown fat cell. This discovery represent new original model to dissect the mystery of this phenomena using PCOS model. Stem cell therapy might potentially be a novel tool for effective treatment of PCOS-related morbidities.