Peroxynitrite could regulate proliferation and neuronal differentiation of neural stem/progenitor cells through activating WNT/β-catenin signaling pathway

Abstract

Background: Hypoxia/ischemia could mediate the differentiation of neural stem/progenitor cells (NSCs) into mature neurons. In hypoxic/ischemic brain, nitric oxide and superoxide are simultaneously produced and they rapidly react to form peroxynitrite. Whether peroxynitrite can regulate neurogenesis is unknown yet.

Objectives: Present study aims to understand the roles of peroxynitrite in regulating self-renewal, proliferation and differentiation of NSCs.

Materials and methods: Primary cultured NSCs were subjected to different stimulations including peroxynitrite donor SIN-1, synthesized peroxynitrite and hypoxia treatment. For visualizing the formation of peroxynitrite, we developed a highly sensitive and specific fluorescent probe and detected the formation of peroxynitrite in the NSCs. We applied different biomarkers including Ki67, BrdU, Tuj1 and DCX, etc./INS; to identify the self-renewal proliferation, and neuronal differentiation of NSCs respectively.

Results: Low concentrations of extraneous peroxynitrite (< 1 μM) promoted NSC/INS; proliferation, self-renewal and neuronal differentiation but high level of peroxynitrite (> 5 μM) induced cytotoxicity. Hypoxic treatment induced the production of peroxynitrite and promoted NSC/INS; proliferation and self-renewal, and neuronal differentiation. Treatments of peroxynitrite decomposition catalysts (PDCs, FeTMPyP and FeTPPS) reduced hypoxia-induced peroxynitrite formation, NSC/INS; proliferation, self-renewal and neuronal differentiation. The neurogenesis promoting effects were partly mediated through activating Wnt/β-catenin signaling pathway.

Conclusion: Low concentration of peroxynitrite may serve as a cellular signaling for promoting NSC/INS; proliferation, self-renewal and neuronal differentiation.

Copyright © 2013 Published by Elsevier B.V.