Oxidative stress increases neurogenesis and oligodendrogenesis in adult neural progenitor cells.
Hydrogen peroxide (H2O2) is a reactive oxygen species that is involved in immunity and neuroinflammation. Here, we investigated whether and how pathophysiological levels of H2O2 influenced the differentiation of neural progenitor cells (NPCs). H2O2 levels within the range measured at neuroinflammatory events were applied to rat primary NPC cultures during 24 h, and effects were assessed directly after exposure or in NPCs that were differentiated for 7 days after H2O2 removal. Exposed differentiated NPCs showed significantly increased numbers of neurons and oligodendrocytes compared with unexposed controls. To identify the possible origin of this differentiation result, we characterized the undifferentiated culture and found a significant increase in both OLIG2(+) cells and proliferative ASCL1(+) C cells that could contribute to both more neurons and oligodendrocytes. In addition, H2O2-induced neurogenesis was supported by western blot and paralleled by gene expression analyses, which revealed an increased expression of the proneural gene Ngn2 and the neuronally expressed gene β-III tubulin. To investigate potential mechanisms for the observed effects on NPC differentiation, we performed gene expression profile analyses for oxidative stress and antioxidant-related and chromatin modification genes where the expression of several important genes was affected by the exposure. Increased oligodendrocyte numbers correlated with increased expression of the chromatin modification enzyme Sirt2, suggesting the involvement of Sirt2 in oligodendrocyte differentiation. Our results suggest a modulatory effect on the differentiation potential of NPCs by H2O2. Our findings indicate that H2O2 exposure has significant effects on NPC proliferation, differentiation, and vulnerability. These results have implications for regeneration after any neuroinflammatory event.
1 Neurology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital , Stockholm, Sweden .
Cynthia
C
Pérez Estrada
Ruxandra
R
Covacu
Sreenivasa R
SR
Sankavaram
Mikael
M
Svensson
Lou
L
Brundin
D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats
D006861:Hydrogen Peroxide