Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the differentiation and function of hematopoietic cells. GM-CSF has been implicated in nervous system function. The goal of the present study was to understand the effects of hypoxia-induced GM-CSF on neural stem cells (NSCs) in a model of spinal cord injury (SCI). GM-CSF-overexpressing NSCs were engineered utilizing a hypoxia-inducible gene expression plasmid, including an Epo enhancer ahead of an SV promoter (EpoSV-GM-CSF). Cells were then subjected to hypoxia (pO 2 , 1%) or a hypoxia-mimicking reagent (CoCl 2 ) in vitro. The progression of time of GM-CSF expression was tracked in EpoSV-GM-CSF-transfected NSCs. Overexpression of GM-CSF in undifferentiated and differentiated NSCs created resistance to H 2 O 2 -induced apoptosis in hypoxia. NSCs transfected with EpoSV-GM-CSF or SV-GM-CSF were transplanted into rats after SCI to assess the effect of GM-CSF on NSC survival and restoration of function. Moreover, a significantly higher amount of surviving NSCs and neuronal differentiation was observed in the EpoSV-GM-CSF-treated group. Significant improvement in locomotor function was also found in this group. Thus, GM-CSF overexpression by the Epo enhancer in hypoxia was beneficial to transplanted NSC survival and to behavioral improvement, pointing toward a possible role for GM-CSF in the treatment of SCI.

CIBZ, a Novel BTB Domain-Containing Protein, Is Involved in Mouse Spinal Cord Injury via Mitochondrial Pathway Independent of p53 Gene

“…Providing CIBZ is medicated in early injury period (4 h–8 h) or used genetically through CIBZ modified neural stem cells (NSCs) [33], it would deter the cell death-induced impairments. Further researches are needed to explore this possibility.…”

GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo

“…GM-CSF acts to mobilize peripheral-blood progenitor cells, resulting in shorter durations of neutropenia in patients receiving induction chemotherapy for hematologic malignancies (25). Further, it is widely appreciated that GM-CSF increases the hematopoietic 18 F-FDG signal and that the heightened signal may persist for weeks after the last dose (16,(26)(27)(28)(29)(30)(31). The findings of this study provide further understanding of the mechanisms underlying this observation.…”

GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice

“…In the CNS, GM-CSF is produced by resident astroglia and T cells, and can also cross the blood-brain and blood-spinal cord barriers where it engages receptors on both immune and neural cells (McLay et al, 1997). GM-CSF affects neuronal plasticity, learning, and memory, and has neurotrophic and anti-apoptotic activities for photoreceptors (Huang et al, 2007, Kim et al, 2012, Krieger et al, 2012, Schallenberg et al, 2012, Kim et al, 2013). In CNS disease states, it is involved in recovery and control of cell death following spinal cord injury (Ha et al, 2005).…”