Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.
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.
Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.Show MeSH
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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).
Affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.