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• W2891179984 abstract "Most of the follicles in human ovaries remain dormant, and only a fraction are mobilized into the growing pool. The growth of these follicles is mediated in part by upregulation of Akt signaling. Insulin-like growth factor 1 (IGF-1) is a potent physiological activator of the AKT pathway. Using our unique xenograft model, we co-transplanted endothelial cells (ECs) that overexpress IGF-1 and achieved both restoration of vascular perfusion and the direct paracrine delivery of IGF-1 in the vicinity of human ovarian tissue. We investigated the potential for ECs expressing IGF-1 to modulate the growth of follicles within the grafts. Xenograft of human ovarian tissue into NSG mice with co-transplantation of control ECs and ECs expressing human IGF-1. To test the modulation of follicles in grafts, we have generated lentiviral vectors expressing human IGF-1. ECs modified by the adenoviral gene fragment E4-ORF1 were transduced with these particles. Xenograft of human ovarian tissue into NSG-oophorectomized mice with co-transplantation of IGF-1 ECs served as the study group. Patient-matched ovarian tissue co-transplanted with non-IGF-1-producing ECs served as controls. We co-transplanted multiple grafts and harvested at 3 (Ctrl, n=10; study, n=9), 8 (Ctrl, n=2; study, n=2), and 14 (Ctrl, n=7; study, n=9) weeks. The ratio of follicles in each treatment was assessed in histologic sections. The study group demonstrated at 3 and 8 weeks a higher proportion of secondary follicles (35.38±9.78 vs. Ctrl 21.36±8.16; p=0.035) and a lower proportion of primary follicles (42.86±5.6 vs. Ctrl 55.49±6.63; p=0.017); no difference was found between the ratios of primordial follicles. Interestingly, at 14 weeks, the proportion of primordial follicles was reduced in the study group (4.73±4.726% vs. Ctrl 22.63±7.04%; p=0.03), while the primary follicle rate was increased (64.27±9.16 vs. Ctrl 50.55±5.29; p=0.05). While there was no difference in the short term, the total number of follicles per mm2 in the study group was lower in the long-term grafts (4±3.6 vs. 7.5±2.05; p=0.05). In this distinctive xenograft model, we have measured the effect of IGF-1 on the growth and development of early-stage follicles that are not responsive to gonadotropins and, therefore, cannot be influenced using conventional in vitro fertilization stimulation protocols. Importantly, long-term exposure resulted in a “burn out” phenotype. Nevertheless, a short-term “molecular stimulation” approach could provide a means of promoting the growth of early stage follicles and fostering their survival to more advanced stages. This approach would benefit patients with unmet need (e.g., poor responders) by optimizing the growth and survival of residual follicles that typically undergo atresia before maturing to the hormone-responsive stages." @default.
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• W2891179984 date "2018-09-01" @default.
• W2891179984 modified "2023-09-30" @default.
• W2891179984 title "Molecular stimulation for promoting growth of early stage follicles by IGF-1" @default.
• W2891179984 doi "https://doi.org/10.1016/j.fertnstert.2018.07.305" @default.
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