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      Electrical Guidance of Human Stem Cells in the Rat Brain

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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.

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          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

          Abstract

          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.

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          Most cited references36

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          Neuronal replacement from endogenous precursors in the adult brain after stroke.

          In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.
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            Corridors of Migrating Neurons in Human Brain and Their Decline during Infancy

            The subventricular zone (SVZ) of many adult non-human mammals generates large numbers of new neurons destined for the olfactory bulb (OB) 1–6 . Along the walls of the lateral ventricles, immature neuronal progeny migrate in tangentially-oriented chains that coalesce into a rostral migratory stream (RMS) connecting the SVZ to the OB. The adult human SVZ, in contrast, contains a hypocellular gap layer separating the ependymal lining from a periventricular ribbon of astrocytes 7 . Some of these SVZ astrocytes can function as neural stem cells in vitro, but their function in vivo remains controversial. An initial report finds few SVZ proliferating cells and rare migrating immature neurons in the RMS of adult humans 7 . In contrast, a subsequent study indicates robust proliferation and migration in the human SVZ and RMS 8,9 . Here, we find that the infant human SVZ and RMS contain an extensive corridor of migrating immature neurons before 18 months of age, but, contrary to previous reports 8 , this germinal activity subsides in older children and is nearly extinct by adulthood. Surprisingly, during this limited window of neurogenesis, not all new neurons in the human SVZ are destined for the OB – we describe a major migratory pathway that targets the prefrontal cortex in humans. Together, these findings reveal robust streams of tangentially migrating immature neurons in human early postnatal SVZ and cortex. These pathways represent potential targets of neurological injuries affecting neonates.
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              Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.

              Wound healing is essential for maintaining the integrity of multicellular organisms. In every species studied, disruption of an epithelial layer instantaneously generates endogenous electric fields, which have been proposed to be important in wound healing. The identity of signalling pathways that guide both cell migration to electric cues and electric-field-induced wound healing have not been elucidated at a genetic level. Here we show that electric fields, of a strength equal to those detected endogenously, direct cell migration during wound healing as a prime directional cue. Manipulation of endogenous wound electric fields affects wound healing in vivo. Electric stimulation triggers activation of Src and inositol-phospholipid signalling, which polarizes in the direction of cell migration. Notably, genetic disruption of phosphatidylinositol-3-OH kinase-gamma (PI(3)Kgamma) decreases electric-field-induced signalling and abolishes directed movements of healing epithelium in response to electric signals. Deletion of the tumour suppressor phosphatase and tensin homolog (PTEN) enhances signalling and electrotactic responses. These data identify genes essential for electrical-signal-induced wound healing and show that PI(3)Kgamma and PTEN control electrotaxis.
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                Author and article information

                Contributors
                Journal
                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                Elsevier
                2213-6711
                29 June 2017
                11 July 2017
                29 June 2017
                : 9
                : 1
                : 177-189
                Affiliations
                [1 ]Departments of Dermatology and Ophthalmology, Institute for Regenerative Cures, University of California Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
                [2 ]Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China
                [3 ]Shanghai Institute of Head Trauma, Shanghai 200127, People's Republic of China
                [4 ]Stem Cell Program and Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA
                [5 ]Aaken Laboratories, Davis, CA 95616, USA
                [6 ]Department of Neurological Surgery, University of California Davis, Davis, CA 95616, USA
                Author notes
                []Corresponding author minzhao@ 123456ucdavis.edu
                Article
                S2213-6711(17)30262-X
                10.1016/j.stemcr.2017.05.035
                5511115
                28669601
                78f080c9-af37-4e31-a0ac-7f26f0b1cdb7
                © 2017 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 13 December 2016
                : 30 May 2017
                : 31 May 2017
                Categories
                Article

                neural stem cells,human neural stem cells,neuroblasts,directional cell migration,electric field,electrotaxis,galvanotaxis,electric stimulation,brain in vivo,in vivo migration

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