The low survival rate of patients with glioblastoma is in part due to the heterogeneity in the cell population of glioblastoma that includes cancer stem cells (CSCs). CSC niches include a hypoxic core that is also closely linked to self-renewal ability, migration, and drug resistance. Here, we report a CSC culture method in three-dimensional microfluidic cell culture devices under gravity-driven perfusion, which we dub hypoxia chips (H-chips). In H-chips, glioblastoma cells, U87, spontaneously formed spheroids within 12 h, even without any addition of growth factors. Compared to monolayer-cultured cells in dishes, spheroids in H-chips showed higher expression of CSC markers, such as hypoxia-inducible factor-1α (HIF-1α), CD133, and nestin. Spheroids in H-chips were more resistant to doxorubicin than monolayer-cultured ones in dishes. Transcriptional profiling revealed that the expression of interleukin-6 (IL-6), one of the inflammatory cytokines, was higher in spheroids in H-chips than in monolayer-cultured cells in dishes. IL-6 depleted cells failed to form spheroids in H-chips, and their drug resistance decreased. These results suggest that in H-chips, glioblastoma cells increased the production of IL-6, and promoted spheroid formation and other cancer stem cell properties, such as drug resistance. Our microfluidic cell culture method is highly useful for recapitulating CSC niches.
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