Towards cell therapy of polycystic ovary syndrome (PCOS): human mesenchymal stem cells secretome inhibits androgen production by pcos theca cells

Abstract

Background & Aim Background Polycystic Ovarian Syndrome (PCOS) is a metabolic disorder characterized by inflammation, infertility and excess ovarian androgen production by theca cells. Though its etiology is not fully understood. Women with PCOS exhibit increased expression of CYP17A1, and CYP11A1 genes involved in androgen production. Due to the robust anti-inflammatory ability of human bone marrow Mesenchymal stem cells (hMSCs), we evaluated its utility as a novel cell-therapy by injecting hMSCs directly into the ovaries of PCOS mouse model. It showed a significant improvement in hyperandrogenemia. hMSCs also secrete various factors in media, known as secretome. The literature shows that the secretome of hMSCs has the same regenerative and reparative function likes hMSCs. Hypothesis We hypothesize that hMSCs secretome contains the factors that are able to inhibit the androgen biosynthesis in PCOS theca cells. Methods, Results & Conclusion Material and Methods Theca cells, collected from normal cycling and PCOS patient underwent ovariectomy, were seeded on culture dishes pre-coated with the extracellular matrix at a density of 6 × 104 cells/ml and cultured for 24 hours. Cells were then treated with either 3T3 conditioned media as a control (C) or Mesenchymal stem cells conditioned media (CM). The C and CM were prepared through collecting the serum-free supernatant of 3T3 and hMSCs at an optimal confluence, 48 hours later. The mRNA and protein expression of CYP17A1, CYP11A1, and DENND1A.V2 were quantified by RT-PCR and Western blot, while testosterone level in media was measured by RIA assay. Results Human PCOS theca cells treated with hMSCs CM for 48 hours secreted significantly lower level of testosterone (146 ± 13.6 ng/dl) compared to control C (215 ± 11.3 ng/dl) (P Conclusion The therapeutic capabilities of hMSCs in PCOS are partially mediated by its secretome which contains various growth factors and anti-inflammatory cytokines both free and within extracellular vesicles. Stem cell therapy, either by cell implantation or via secretome injection might potentially be a novel approach for effective treatment of PCOS patients.