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Summary Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies., Graphical Abstract, Highlights • Developed a technology and device delivering electric current to the brain in vivo • Achieved stable delivery of currents to brain with monitoring and safety concerns • Exhibited effective guidance of migration of transplanted human NSCs in live brain • Demonstrated enhanced motility, survival, and differentiation of the guided hNSCs, In this article, Zhao and colleagues report a novel technology delivering directional electric currents which mobilizes and guides human neural stem cells through the brain in vivo, demonstrating an effective and safe approach to facilitate stem cell therapy, with significant implications for a wide range of brain diseases.

Endogenous electrical fields (EFs) at corneal and skin wounds send a powerful signal that directs cell migration during wound healing. This signal therefore may serve as a fundamental regulator directing cell polarization and migration. Very little is known of the intracellular and molecular mechanisms that mediate EF-induced cell polarization and migration. Here, we report that Chinese hamster ovary (CHO) cells show robust directional polarization and migration in a physiological EF (0.3-1 V/cm) in both dissociated cell culture and monolayer culture. An EF of 0.6 V/cm completely abolished cell migration into wounds in monolayer culture. An EF of higher strength (≥1 V/cm) is an overriding guidance cue for cell migration. Application of EF induced quick phosphorylation of glycogen synthase kinase 3β (GSK-3β) which reached a peak as early as 3 min in an EF. Inhibition of protein kinase C (PKC) significantly reduced EF-induced directedness of cell migration initially (in 1-2 h). Inhibition of GSK-3β completely abolished EF-induced GA polarization and significantly inhibited the directional cell migration, but at a later time (2-3 h in an EF). Those results suggest that GSK-3β is essential for physiological EF-induced Golgi apparatus (GA) polarization and optimal electrotactic cell migration.

The endogenous electric field may provide an important signal for directional cell migration during cancer metastasis but the mechanism of cell electrotaxis is poorly understood. It was postulated that microtubules play a central role in the polarization and directional migration of several types of cells. In this paper we investigated the role of microtubules in electrotaxis of rat Walker carcinosarcoma WC256 cells. We found that colchicine-stimulated disassembly of microtubules caused the formation of blebs instead of lamellipodia at the front of about 45% of cells. Most of the remaining cells contracted and became rounded or transformed into non-polar cells. Depolymerization of microtubules in both subpopulations of cells reduced the directionality of cell migration to about 50% of the control, but bleb- forming cells migrated much more efficiently than lamellipodia-forming cells. The analysis of microtubules architecture in the presence of an endogenous electric field showed that there is no relationship between the direction of migration and the polarization of microtubules. These results suggest that microtubules are not indispensable for electrotaxis of WC256 cells, however they may improve the directionality of cell migration.