Inhibition of neuronal nitric oxide synthase activity promotes migration of human-induced pluripotent stem cell-derived neural stem cells toward cancer cells.
The breakthrough in derivation of human-induced pluripotent stem cells (hiPSCs) provides an approach that may help overcome ethical and allergenic challenges posed in numerous medical applications involving human cells, including neural stem/progenitor cells (NSCs). Considering the great potential of NSCs in targeted cancer gene therapy, we investigated in this study the tumor tropism of hiPSC-derived NSCs and attempted to enhance the tropism by manipulation of biological activities of proteins that are involved in regulating the migration of NSCs toward cancer cells. We first demonstrated that hiPSC-NSCs displayed tropism for both glioblastoma cells and breast cancer cells in vitro and in vivo. We then compared gene expression profiles between migratory and non-migratory hiPSC-NSCs toward these cancer cells and observed that the gene encoding neuronal nitric oxide synthase (nNOS) was down-regulated in migratory hiPSC-NSCs. Using nNOS inhibitors and nNOS siRNAs, we demonstrated that this protein is a relevant regulator in controlling migration of hiPSC-NSCs toward cancer cells, and that inhibition of its activity or down-regulation of its expression can sensitize poorly migratory NSCs and be used to improve their tumor tropism. These findings suggest a novel application of nNOS inhibitors in neural stem cell-mediated cancer therapy.
['Chen|Can|C|', 'Wang|Yi|Y|', 'Goh|Sally S L|SS|', 'Yang|Jing|J|', 'Lam|Dang Hoang|DH|', 'Choudhury|Yukti|Y|', 'Tay|Felix Chang|FC|', 'Du|Shouhui|S|', 'Tan|Wee Kiat|WK|', 'Purwanti|Yovita Ida|YI|', 'Fan|Weimin|W|', 'Wang|Shu|S|']
D000818:Animals D045744:Cell Line, Tumor D002465:Cell Movement D005260:Female D055785:Gene Knockdown Techniques D006801:Humans D057026:Induced Pluripotent Stem Cells D051379:Mice D008819:Mice, Nude D009369:Neoplasms D058953:Neural Stem Cells D052248:Nitric Oxide Synthase Type I D020411:Oligonucleotide Array Sequence Analysis D060888:Real-Time Polymerase Chain Reaction D059467:Transcriptome
neuronal nitric oxide synthase Neural stem cells tumor tropism Boyden chamber assay microarray analysis