Beneficial Compaction of Spinal Cord Lesion by Migrating Astrocytes Through Glycogen Synthase Kinase-3 Inhibition

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2011 Sep 8

PMID 21898827

Citations 34

Authors

Francois Renault-Mihara

Hiroyuki Katoh

Takeshi Ikegami

Akio Iwanami

Masahiko Mukaino

Akimasa Yasuda

Satoshi Nori

Yo Mabuchi

Hirobumi Tada

Shinsuke Shibata

Ken Saito

Masayuki Matsushita

Kozo Kaibuchi

Seiji Okada

Yoshiaki Toyama

Masaya Nakamura

Hideyuki Okano

Affiliations

Soon will be listed here.

Abstract

The migratory response of astrocytes is essential for restricting inflammation and preserving tissue function after spinal cord injury (SCI), but the mechanisms involved are poorly understood. Here, we observed stimulation of in vitro astrocyte migration by the new potent glycogen synthase kinase-3 (GSK-3) inhibitor Ro3303544 and investigated the effect of Ro3303544 administration for 5 days following SCI in mice. This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery. Moreover, the decreased extent of chondroitin sulphate proteoglycans and collagen IV demonstrated that scarring was reduced in Ro3303544-treated mice. 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.

Citing Articles

Histological effects of combined therapy involving scar resection, decellularized scaffolds, and human iPSC-NS/PCs transplantation in chronic complete spinal cord injury.

Ito K, Shinozaki M, Hashimoto S, Saijo Y, Suematsu Y, Tanaka T Sci Rep. 2024; 14(1):31500.

PMID: 39733145 PMC: 11682313. DOI: 10.1038/s41598-024-82959-7.

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation.

Zhao N, Chen X, Chen Q, Liu X, Geng F, Zhu M Zool Res. 2024; 45(4):857-874.

PMID: 39004863 PMC: 11298670. DOI: 10.24272/j.issn.2095-8137.2024.085.

Unravelling the Road to Recovery: Mechanisms of Wnt Signalling in Spinal Cord Injury.

Ganesan S, Dharmarajan A, Sudhir G, Perumalsamy L Mol Neurobiol. 2024; 61(10):7661-7679.

PMID: 38421469 DOI: 10.1007/s12035-024-04055-1.

A closed-body preclinical model to investigate blast-induced spinal cord injury.

Norris C, Weatherbee J, Murphy S, Marquetti I, Maniakhina L, Boruch A Front Mol Neurosci. 2023; 16:1199732.

PMID: 37383427 PMC: 10293620. DOI: 10.3389/fnmol.2023.1199732.

Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors.

Ma X, Yang T, Liu L, Peng X, Qian F, Tang F Biomolecules. 2023; 13(5).

PMID: 37238624 PMC: 10216700. DOI: 10.3390/biom13050754.

References

Xia Y, Zhao T, Li J, Li L, Hu R, Hu S . Antisense vimentin cDNA combined with chondroitinase ABC reduces glial scar and cystic cavity formation following spinal cord injury in rats. Biochem Biophys Res Commun. 2008; 377(2):562-566. DOI: 10.1016/j.bbrc.2008.10.024. View

Renault-Mihara F, Okada S, Shibata S, Nakamura M, Toyama Y, Okano H . Spinal cord injury: emerging beneficial role of reactive astrocytes' migration. Int J Biochem Cell Biol. 2008; 40(9):1649-53. DOI: 10.1016/j.biocel.2008.03.009. View

Salicioni A, Gaultier A, Brownlee C, Cheezum M, Gonias S . Low density lipoprotein receptor-related protein-1 promotes beta1 integrin maturation and transport to the cell surface. J Biol Chem. 2003; 279(11):10005-12. DOI: 10.1074/jbc.M306625200. View

Iannotti C, Zhang Y, Shields L, Han Y, Burke D, Xu X . Dural repair reduces connective tissue scar invasion and cystic cavity formation after acute spinal cord laceration injury in adult rats. J Neurotrauma. 2006; 23(6):853-65. DOI: 10.1089/neu.2006.23.853. View

Adachi K, Mirzadeh Z, Sakaguchi M, Yamashita T, Nikolcheva T, Gotoh Y . Beta-catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone. Stem Cells. 2007; 25(11):2827-36. DOI: 10.1634/stemcells.2007-0177. View

Sofroniew M . Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009; 32(12):638-47. PMC: 2787735. DOI: 10.1016/j.tins.2009.08.002. View

Tsuji O, Miura K, Okada Y, Fujiyoshi K, Mukaino M, Nagoshi N . Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci U S A. 2010; 107(28):12704-9. PMC: 2906548. DOI: 10.1073/pnas.0910106107. View

Dimilla P, Barbee K, Lauffenburger D . Mathematical model for the effects of adhesion and mechanics on cell migration speed. Biophys J. 1991; 60(1):15-37. PMC: 1260035. DOI: 10.1016/S0006-3495(91)82027-6. View

Okano H . Neural stem cells and strategies for the regeneration of the central nervous system. Proc Jpn Acad Ser B Phys Biol Sci. 2010; 86(4):438-50. PMC: 3417805. DOI: 10.2183/pjab.86.438. View

10.

Myer D, Gurkoff G, Lee S, Hovda D, Sofroniew M . Essential protective roles of reactive astrocytes in traumatic brain injury. Brain. 2006; 129(Pt 10):2761-72. DOI: 10.1093/brain/awl165. View

11.

Le Q, Denko N, Giaccia A . Hypoxic gene expression and metastasis. Cancer Metastasis Rev. 2004; 23(3-4):293-310. DOI: 10.1023/B:CANC.0000031768.89246.d7. View

12.

Araujo H, Danziger N, Cordier J, Glowinski J, Chneiweiss H . Characterization of PEA-15, a major substrate for protein kinase C in astrocytes. J Biol Chem. 1993; 268(8):5911-20. View

13.

Takada Y, Ye X, Simon S . The integrins. Genome Biol. 2007; 8(5):215. PMC: 1929136. DOI: 10.1186/gb-2007-8-5-215. View

14.

Klapka N, Muller H . Collagen matrix in spinal cord injury. J Neurotrauma. 2006; 23(3-4):422-35. DOI: 10.1089/neu.2006.23.422. View

15.

Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K . Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009; 27(8):743-5. DOI: 10.1038/nbt.1554. View

16.

Fitch M, Doller C, Combs C, Landreth G, Silver J . Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci. 1999; 19(19):8182-98. PMC: 6783021. View

17.

Kapoor M, Liu S, Shi-Wen X, Huh K, McCann M, Denton C . GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1-dependent mechanism. J Clin Invest. 2008; 118(10):3279-90. PMC: 2542848. DOI: 10.1172/JCI35381. View

18.

Bush T, Puvanachandra N, Horner C, Polito A, Ostenfeld T, Svendsen C . Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron. 1999; 23(2):297-308. DOI: 10.1016/s0896-6273(00)80781-3. View

19.

Flugel D, Gorlach A, Michiels C, Kietzmann T . Glycogen synthase kinase 3 phosphorylates hypoxia-inducible factor 1alpha and mediates its destabilization in a VHL-independent manner. Mol Cell Biol. 2007; 27(9):3253-65. PMC: 1899978. DOI: 10.1128/MCB.00015-07. View

20.

Fancy S, Baranzini S, Zhao C, Yuk D, Irvine K, Kaing S . Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev. 2009; 23(13):1571-85. PMC: 2704469. DOI: 10.1101/gad.1806309. View