Oxygen tension modulates neurite outgrowth in PC12 cells through a mechanism involving HIF and VEGF.
Cell-based approaches are a promising therapeutic strategy for treating injuries to the nervous system, but the optimal means to promote neurite extension and direct cellular behavior are unclear. Previous studies have examined the behavior of neural-like cells in ambient air (21% oxygen tension), yet these conditions are not representative of the physiological oxygen microenvironment of neural tissues. We hypothesized that neuronal differentiation of a model neural cell line (PC12) could be controlled by modulating local oxygen tension. Compared to ambient conditions, PC12 cells cultured in reduced oxygen exhibited significant increases in neurite extension and total neurite length, with 4% oxygen yielding the highest levels of both indicators. We confirmed neurite extension was mediated through oxygen-responsive mechanisms using small molecules that promote or inhibit HIF-1alpha stabilization. The hypoxic target gene Vegf was implicated as a neurotrophic factor, as neurite formation at 21% oxygen was mimicked with exogenous VEGF, and a VEGF-neutralizing antibody attenuated neurite formation under reduced oxygen conditions. These findings demonstrate that behavior of neural-like cells is driven by the oxygen microenvironment via VEGF function, and suggest promising approaches for future applications in neural repair.
Genetos
Damian C
DC
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
Cheung
Whitney K
WK
Decaris
Martin L
ML
Leach
J Kent
JK
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D010100:Oxygen / Q000378:metabolism*; D016716:PC12 Cells / Q000166:cytology / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042442:Vascular Endothelial Growth Factors; D010100:Oxygen