Abstract
BACKGROUND: Premature ovarian insufficiency (POI) can cause multiple sequelae in young women and is currently incurable. Mesenchymal stem cell (MSC)-based treatment of POI shows great promise. However, some limitations affect their efficacy in POI treatment, and exploration of methods to improve their efficacy is necessary. This study aimed to explore whether Rg1 can improve the efficacy of human amnion-derived MSC (hAD-MSC) transplantation in the treatment of rats with chemotherapy-induced POI. METHODS: hAD-MSCs were isolated from human amnions. One hundred female SD rats were divided into control, POI, Rg1, hAD-MSCs and Rg1 + hAD-MSCs groups. POI rat models were first established by intraperitoneal injection of cisplatin, and then the rats in the hAD-MSCs and Rg1 + hAD-MSCs groups were injected with PKH26-labelled hAD-MSCs via tail veins, while the rats in the Rg1 and Rg1 + hAD-MSCs groups were intraperitoneally injected with Rg1. At 24 h, 4 and 8 weeks after cell transplantation, serum sex hormone levels, oestrous cycles, ovarian pathological changes, granulosa cell (GC) apoptosis and antiapoptotic and proapoptotic protein expression in ovaries were evaluated. A chemotherapy-induced injury model of GCs was established by treatment with cisplatin in vitro to investigate the underlying mechanisms. RESULTS: hAD-MSC transplantation significantly increased Bcl-2 expression; decreased Bax, cleaved-caspase-3, cleaved-caspase-9 and cleaved-PARP expression; and inhibited GC apoptosis in POI ovaries, which reduced ovarian injury and improved ovarian function in chemotherapy-induced POI rats; and the effects of hAD-MSC transplantation were significantly improved by Rg1 combined with hAD-MSC transplantation. Moreover, the enhanced efficacy of hAD-MSCs by Rg1 combined with hAD-MSCs in the inhibition of ovarian GC apoptosis was demonstrated in a chemotherapy injury model of GCs induced by cisplatin in vitro. The mechanisms might involve the modulatory role of Rg1 on both transplanted hAD-MSCs and GCs in the ovaries of POI rats, which indirectly and directly promoted the antiapoptotic effects on ovarian GCs, respectively, and the PI3K/Akt-mitochondrial intrinsic pathway of apoptosis may be a vital target pathway involved in these processes. CONCLUSION: Rg1 may promote the efficacy of hAD-MSC transplantation in alleviating chemotherapy-induced POI in rats. Rg1 might be a novel adjuvant drug to promote the efficacy of MSCs in the treatment of chemotherapy-induced POI.