Abstract

The Impact of Methotrexate on Neural Stem Cells and the Protection Provided by Cells in the Neurogenic Niche

While the survival rates for cancer have dramatically increased with the use of chemotherapy, substantial numbers of patients complain of cognitive impairments associated with this treatment. These symptoms are known as “chemobrain” and include loss of concentration and memory associated with poor work performance. One cause of chemobrain appears to be a decrease in the neural stem cell proliferation essential for adult hippocampal neurogenesis. This produces new neurons required for memory consolidation. Neural stem cell proliferation occurs in a stem cell niche within the sub granular zone (SGZ) of the dentate gyrus. Recent in vivo studies have shown that in the SGZ, neural stem cells associated with blood vessels survive chemotherapy better than those not in contact with the vasculature. Our in vitro study tested the effect of Methotrexate (MTX) on dividing neural stem cells and brain endothelial cells separately and when co-cultured in contact with one another. The results, using MTT assays, show that neural cells are significantly more sensitive to MTX than endothelial cells. Marked neural cells were then cultured on a mono layer of either endothelial or non-neural cells (3T3 fibroblasts) and treated with MTX. Co-culture with endothelial cells offered significant protection from MTX compared with culture with non-neural cells or neural cells on their own. This in vitro model replicates in vivo observations and can be used to study the protective role of endothelial cells on neural stem cells. An understanding of this may be used to preserve hippocampal neurogenesis and reduce the incidence of chemobrain. 

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