Aquaporin-7 Facilitates Proliferation and Adipogenic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Regulating Hydrogen Peroxide Transport

Hydrogen peroxide (H₂O₂) is a major form of reactive oxygen species that play an important role in the survival, proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). The regulatory mechanisms of H₂O₂ homeostasis in BMSCs are not fully understood. Here we demonstrate for the first time that aquaglyceroporin AQP7 is a functional peroxiporin expressed in BMSCs and remarkably upregulated upon adipodenic induction. The proliferation ability of BMSCs from AQP7^-/- mice was significantly decreased, as indicated by fewer clonal formation and cell cycle arrest compared with wildtype BMSCs. AQP7 deficiency caused accumulation of intracellular generated H₂O₂ during BMSCs proliferation, leading to oxidative stress and inhibition of PI3K/AKT and STAT3 signaling pathways. After adipogenic induction, however, the AQP7^-/- BMSCs exhibited greatly reduced adipogenic differentiation with fewer lipid droplets formation and lower cellular triglycerides content than wildtype BMSCs. In such case AQP7 deficiency was found to diminish import of extracellular H₂O₂ produced by plasma membrane NADPH Oxidases, resulting in altered AMPK and MAPK signaling pathways and reduced expression of lipogenic genes C/EBPα and PPARγ. Our data revealed a novel regulatory mechanism of BMSCs function through AQP7-mediated H₂O₂ transport across plasma membrane. AQP7 is a peroxiporin mediating H₂O₂ transport across the plasma membrane of BMSCs. During proliferation, AQP7 deficiency results in accumulation of intracellular generated H₂O₂ due to reduced export, which inhibited STAT3 and PI3K/AKT/insulin receptor signaling pathways and cell proliferation. During adipogenic differentiation, however, AQP7 deficiency blocked the uptake of extracelluar H₂O₂ generated through plasma membrane NOX enzymes. The reduced intracellular H₂O₂ level causes decreased expression of lipogenic genes C/EBPα and PPARγ due to altered AMPK and MAPK signaling pathways, leading to impaired adipogenic differentiation.