Alleviative Effects of Adipose Tissue-derived Stem Cells and -NETA on Metabolic, Biochemical, and Endocrine Parameters in a Letrozole-induced Rat Model of PCOS

Background: Polycystic ovary syndrome (PCOS), the most prevalent reproductive disorder, is accompanied by hyperandrogenism (HA), ovulatory dysfunction (OD), and insulin resistance (IR). A number of reports indicate that adipokines play a vital role in the pathophysiology of PCOS. One of these adipokines is chemerin, which is engaged in metabolic disorders, especially obesity, diabetes, and PCOS. Based on the data, the circulating levels of chemerin and the expression of chemokine-like receptor-1 (CMKLR1) in white adipose tissue (WAT) of women with PCOS are significantly higher than in healthy ones. Currently, several scholars have emphasized the therapeutic capacities of stem cells, notably mesenchymal stem cells (MSCs), for the treatment of PCOS. Objective: In this study, for the first time, the impacts of 2-(alpha-naphthoyl) ethyltrimethylammonium iodide (alpha-NETA), an antagonist of CMKLR1, adipose-derived stem cells (ADSCs), and their combinations on metabolic and endocrine aberrancies were assessed in the WAT and ovarian tissues of the letrozole (LET)-induced PCOS rats. Methods: In the current study, 30 Wistar rats were randomly divided into five groups: control (n = 6), LET-induced PCOS (1.5 mg/kg p.o., n = 6), LET + ADSCs (10(6) ADSCs i.v., n = 6), LET + alpha-NETA (10 mg/kg p.o., n = 6), and LET + ADSCs + alpha-NETA (n = 6). The blood samples and adipose and ovarian tissues were obtained to evaluate the effects of ADSCs and alpha-NETA on hormonal and metabolic parameters in the PCOS rats. Results: Our findings showed that the administration of alpha-NETA, ADSCs, and the combination of both favorably restored the irregular estrus cycle and considerably modulated the endocrine parameters in PCOS rats. In addition, these therapeutic factors remarkably regulated steroidogenic and adipogenic gene expressions, as well as the genes related to glucose metabolism and brown adipose tissue (BAT) markers in these animals. Conclusion: These findings indicate that the combination of ADSCs and alpha-NETA can successfully ameliorate metabolic and endocrine dysfunction in LET-induced PCOS rats, and this strategy could be a new therapeutic choice for patients with PCOS.