TNF-α and IFN-γ prestimulation enhances the therapeutic efficacy of human amniotic epithelial stem cells in chemotherapy-induced ovarian dysfunction

作者：Yating Huang, Qiu-Wan Zhang, Wenjiao Cao, Qin-Yu Zhang, Lu-Lu Wang, D. Lai · 发表于：Inflammation and Regeneration · 年份：2023 · DOI：10.1186/s41232-023-00309-y · 被引用次数：14 · 研究领域：Medicine

Background Exposure to a harsh ovarian microenvironment induced by chemotherapeutic agents seriously affects the remodeling of ovarian function and follicular development, leading to premature ovarian failure or insufficiency (POF/POI). For decades, the effectiveness of stem cell therapies in POI animal models has been intensively studied; however, strategies to enhance the therapeutic effect of stem cells remain challenging. Methods In this study, we first observed the pathological changes of the ovaries at different time points during chemotherapy, including the number of follicles, granulosa cell proliferation, oxidative stress damage, ovarian fibrosis, and inflammatory reaction. Moreover, we investigated whether activated hAECs stimulated by the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were more effective than native hAECs in repairing ovarian injury induced by chemotherapy. Results The inhibitory effect of chemotherapy drugs on ovarian granulosa cells (GCs) in growing follicles mainly occurred on day 3 after chemotherapy in a mouse model. Then, continued ovarian injury, including oxidative damage and cell death cascades, resulted in the depletion of follicular reserves and inflammation-related ovarian fibrosis. Cytokine array demonstrated that activated hAECs secreted high levels of paracrine cytokines related to extracellular matrix (ECM) remodeling, angiogenesis, and immunomodulation. An in vivo study showed that the engraftmen...