Peroxynitrite enhances self-renewal and neuronal differentiation of neural stem/progenitor cells

Abstract

Neural stem/progenitor cells (NSCs) have limited capacities of growth and differentiation, offering possible regeneration therapy for stroke and neurodegenerative diseases. Hypoxic/ischemic stimulation mediates the growth and differentiation of NSCs into mature neurons. In hypoxic/ischemic brain, nitric oxide and superoxide are simultaneously produced and they rapidly react to form peroxynitrite. Peroxynitrite has been considered to be responsible for neurotoxicity after stroke for long time. However, recent studies indicate low concentrations of peroxynitrite promote endothelial cell growth for angiogenesis angiogenesis and contribute to hypoxia-induced muscle cell proliferation. Here, we investigated peroxynitrite function in neural stem/progenitors cells. Somewhat surprisingly, with our new sensitive and specific peroxynitrite probe HKYellow-AM, we found that cells maintained an endogenous relative high peroxynitrite level showed the more potent capacity of proliferation and self-renewal. Low concentrations of exogenous peroxynitrite promoted NSCs proliferation, self-renewal and neuronal differentiation. Increased peroxynitrite during hypoxia was visualized HKYellow-AM staining. Meanwhile, peroxynitrite decomposition catalysts (PDCs, FeTMPyP and FeTPPS) treatment reduced hypoxia-induced peroxynitrite formation, NSCs proliferation, self-renewal and neuronal differentiation. Moreover, effects of peroxynitrite on neurogenesis were partly through activating HIF-1α correlated with enhanced Wnt/β-catenin signaling pathway. These results suggest that peroxynitrite may serves as a cellular signal for promoting NSCs proliferation, self-renewal and neuronal differentiation.