Placental Growth Factor Secreted from Placenta-Derived Mesenchymal Stem Cells Improves Ovarian Function in TAA-Injured Rats via Antioxidant Effects

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Ovarian dysfunction resulting from metabolic or toxic injury is characterized by follicular depletion, stromal remodeling, oxidative stress, and endocrine dysregulation. Placenta-derived mesenchymal stem cells (PD-MSCs) have been proposed as a potential therapeutic approach due to their paracrine factors, including placental growth factor (PlGF). However, the pathways through which PD-MSCs exert protective effects on the ovary remain insufficiently defined. In this study, we examined whether PD-MSC transplantation ameliorates ovarian injury in a thioacetamide (TAA)-induced ovarian insufficiency model and explored the signaling events potentially associated with this response. Female rats were administered TAA for 12 weeks, and PD-MSCs were transplanted at week 8. We assessed ovarian morphology, fibrosis, oxidative stress markers, hormonal profiles, and follicle development. Complementary in vitro experiments using TAA-treated KGN granulosa-like cells were performed to investigate potential mechanistic associations. PD-MSC transplantation improved ovarian architecture, reduced collagen deposition, enhanced follicle growth, and mitigated oxidative stress. These changes were accompanied by increased PlGF expression and enhanced activation of fms-like tyrosine kinase-1 (Flt-1), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related antioxidant pathways. In vitro, PD-MSCs coculture similarly attenuated oxidative stress and partially improved mitochondrial membrane potential in damaged KGN cells. Together, these findings suggest that PD-MSCs ameliorate ovarian structural damage and oxidative stress in TAA-induced injury, potentially through paracrine mechanisms partly involving PlGF/Flt-1-associated antioxidant signaling. This work supports the therapeutic potential of PD-MSCs for metabolic or toxicant-induced ovarian insufficiency while underscoring the need for further studies to fully delineate the specific contribution of PlGF and its interaction with downstream antioxidant pathways.

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