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Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.

Renault-Mihara F, Katoh H, Ikegami T, Iwanami A, Mukaino M, Yasuda A, Nori S, Mabuchi Y, Tada H, Shibata S, Saito K, Matsushita M, Kaibuchi K, Okada S, Toyama Y, Nakamura M, Okano H - EMBO Mol Med (2011)

Bottom Line: This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery.A variety of in vitro and in vivo experiments further suggested that GSK-3 inhibition stimulated astrocyte migration by decreasing adhesive activity via reduced surface expression of β1-integrin.Our results reveal a novel benefit of GSK-3 inhibition for SCI and suggest that the stimulation of astrocyte migration is a feasible therapeutic strategy for traumatic injury in the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

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Sustained, but not acute, inhibition of GSK-3 by Ro3303544 stimulates the migration of astrocytes and reduces their spreading in vitroTreatment for 24 h with 1 µM Ro3303544 resulted in the strong nuclear accumulation of β-catenin in astrocytes (white arrowheads). Scale bar: 20 µm.The sustained inhibition of GSK-3 by 48-h pretreatment with either Ro3303544 or SB415286 greatly increased astrocyte migration in a transwell assay. Wash-out of Ro3303544 normalized the migration index. Data represent mean ± SD of three independent experiments. ***p < 0.001.Pretreatment for 48 h with Ro3303544 before seeding reduced the spreading of astrocytes onto coverslips coated with 10 µg/ml laminin. Green: F-actin labelled with phalloidin; red: α-tubulin; blue: Hoechst nuclear staining. Scale bars: 50 µm.
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fig02: Sustained, but not acute, inhibition of GSK-3 by Ro3303544 stimulates the migration of astrocytes and reduces their spreading in vitroTreatment for 24 h with 1 µM Ro3303544 resulted in the strong nuclear accumulation of β-catenin in astrocytes (white arrowheads). Scale bar: 20 µm.The sustained inhibition of GSK-3 by 48-h pretreatment with either Ro3303544 or SB415286 greatly increased astrocyte migration in a transwell assay. Wash-out of Ro3303544 normalized the migration index. Data represent mean ± SD of three independent experiments. ***p < 0.001.Pretreatment for 48 h with Ro3303544 before seeding reduced the spreading of astrocytes onto coverslips coated with 10 µg/ml laminin. Green: F-actin labelled with phalloidin; red: α-tubulin; blue: Hoechst nuclear staining. Scale bars: 50 µm.

Mentions: Inhibition of GSK-3 by Ro3303544 was found to compromise the recolonization of a wounded area (Supporting Information, Fig S1A and Supplemental Movie 1), in agreement with the role of GSK-3 in polarization (Etienne-Manneville & Hall, 2003). Sustained GSK-3 inhibition before the migration assay was reasoned to be necessary for activating β-catenin-responsive genes. Treatment for 24 h with Ro3303544 resulted in the nuclear accumulation of β-catenin in astrocytes (Fig 2A) in a dose-dependent manner (Fig S2A and S2B). In agreement with the mitogenic effect of activated β-catenin in various cell types, these doses of Ro3303544 were observed to promote bromodeoxyuridine (BrdU) incorporation in astrocytes in vitro (Fig S2C).


Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.

Renault-Mihara F, Katoh H, Ikegami T, Iwanami A, Mukaino M, Yasuda A, Nori S, Mabuchi Y, Tada H, Shibata S, Saito K, Matsushita M, Kaibuchi K, Okada S, Toyama Y, Nakamura M, Okano H - EMBO Mol Med (2011)

Sustained, but not acute, inhibition of GSK-3 by Ro3303544 stimulates the migration of astrocytes and reduces their spreading in vitroTreatment for 24 h with 1 µM Ro3303544 resulted in the strong nuclear accumulation of β-catenin in astrocytes (white arrowheads). Scale bar: 20 µm.The sustained inhibition of GSK-3 by 48-h pretreatment with either Ro3303544 or SB415286 greatly increased astrocyte migration in a transwell assay. Wash-out of Ro3303544 normalized the migration index. Data represent mean ± SD of three independent experiments. ***p < 0.001.Pretreatment for 48 h with Ro3303544 before seeding reduced the spreading of astrocytes onto coverslips coated with 10 µg/ml laminin. Green: F-actin labelled with phalloidin; red: α-tubulin; blue: Hoechst nuclear staining. Scale bars: 50 µm.
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Related In: Results  -  Collection

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fig02: Sustained, but not acute, inhibition of GSK-3 by Ro3303544 stimulates the migration of astrocytes and reduces their spreading in vitroTreatment for 24 h with 1 µM Ro3303544 resulted in the strong nuclear accumulation of β-catenin in astrocytes (white arrowheads). Scale bar: 20 µm.The sustained inhibition of GSK-3 by 48-h pretreatment with either Ro3303544 or SB415286 greatly increased astrocyte migration in a transwell assay. Wash-out of Ro3303544 normalized the migration index. Data represent mean ± SD of three independent experiments. ***p < 0.001.Pretreatment for 48 h with Ro3303544 before seeding reduced the spreading of astrocytes onto coverslips coated with 10 µg/ml laminin. Green: F-actin labelled with phalloidin; red: α-tubulin; blue: Hoechst nuclear staining. Scale bars: 50 µm.
Mentions: Inhibition of GSK-3 by Ro3303544 was found to compromise the recolonization of a wounded area (Supporting Information, Fig S1A and Supplemental Movie 1), in agreement with the role of GSK-3 in polarization (Etienne-Manneville & Hall, 2003). Sustained GSK-3 inhibition before the migration assay was reasoned to be necessary for activating β-catenin-responsive genes. Treatment for 24 h with Ro3303544 resulted in the nuclear accumulation of β-catenin in astrocytes (Fig 2A) in a dose-dependent manner (Fig S2A and S2B). In agreement with the mitogenic effect of activated β-catenin in various cell types, these doses of Ro3303544 were observed to promote bromodeoxyuridine (BrdU) incorporation in astrocytes in vitro (Fig S2C).

Bottom Line: This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery.A variety of in vitro and in vivo experiments further suggested that GSK-3 inhibition stimulated astrocyte migration by decreasing adhesive activity via reduced surface expression of β1-integrin.Our results reveal a novel benefit of GSK-3 inhibition for SCI and suggest that the stimulation of astrocyte migration is a feasible therapeutic strategy for traumatic injury in the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus