Intervention of chemotherapy-induced ovarian failure/infertility using diploid cell therapy

Abstract

To determine if diploid cell therapy can restore function to chemotherapy (CTX)-induced ovarian failure (OF). A prospective study was used to assess the ability of diploid cell therapy to restore fertility to CTX-treated adult SV129 female mice. Experiment (Expt) 1: mice were injected with 12mg/kg busulfan + 120mg/kg cyclophosphamide (CTX) or vehicles (DMSO + saline) and challenged 7 days later with equine gonadotropin to determine the effect of CTX on folliculogenic activities at proestrus. Expt 2: mice were assigned to 3 groups (gps) A, B and C. OF was induced in mice in gps A and B as in expt 1. 7 days later, gp A mice each received 2 x 106 syngeneic nucleated peripheral blood cells (NPBC). Gp B and C mice received saline and CTX vehicles, respectively. Breeding was initiated and litter size used to assess fertility. The number of primordial (Prm, 183.5 + 10.4) and antral (Ant, 5.3 + 1.4) follicles were lower (P<0.001) in CTX-treated versus control (Prm, 365.8 + 3.7; Ant, 26.8 + 2.6) mice. CTX-treated mice ovulated fewer (P< 0.001) eggs in response to hCG compared with controls, with the percentage of degenerate/immature eggs higher (23%; P<0.01) in CTX-treated versus controls (11.0%). Using superarray analysis, ovaries from CTX treated mice exhibited increased mRNA expression for MaP4k1, LRMP and ERAF compared with those of controls. As expected, gp B mice sustained OF and reduced (P<0.05) liter size (1.8 + 0.6 pups) compared to mice in gp C (6.8 + 1.3 pups). Interestingly, the litter size in dams in gp A (4.5 + 0.7 pups) was higher (P<0.05) than that of dams in gp B but comparable to that of dams in the gp C. This study shows a successful restoration of fertility to CTX-treated mice by diploid cell therapy.