Astrocytes attenuate oligodendrocyte death in vitro through an alpha(6) integrin-laminin-dependent mechanism.
Oligodendrocyte (OL) death occurs in many disorders of the CNS, including multiple sclerosis and brain trauma. Factors reported to induce OL death include deprivation of growth factors, elevation of cytokines, oxidative stress, and glutamate excitotoxicity. Because astrocytes produce a large amount of growth factors and antioxidants and are a major source of glutamate uptake, we tested the hypothesis that astrocytes may have a protective role for OL survival. We report that when OLs from the adult mouse brain were initiated into tissue culture, DNA fragmentation and chromatin condensation resulted, indicative of apoptosis. OL death was significantly reduced in coculture with astrocytes, but not with fibroblasts, which provided a similar monolayer of cells as astrocytes. The protection of OL demise by astrocytes was not reproduced by its conditioned medium and was not accounted for by several neurotrophic factors. In contrast, interference with the alpha(6) integrin subunit, but not the alpha(1), alpha(2), alpha(3), alpha(4), alpha(5), or alpha(v) integrin chains, negated astrocyte protection of OLs. Furthermore, a function-blocking antibody to alpha(6)beta(1) integrin reduced the ability of astrocytes to promote OL survival. The extracellular matrix ligand for alpha(6)beta(1) is laminin, which is expressed by astrocytes. Significantly, neutralizing antibodies to laminin-2 and laminin-5 inhibited the astrocyte mediation of OL survival. These results implicate astrocytes in promoting OL survival through a mechanism involving the interaction of alpha(6)beta(1) integrin on OLs with laminin on astrocytes. Enhancing this interaction may provide for OL survival in neurological injury.
Corley
S M
SM
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Ladiwala
U
U
Besson
A
A
Yong
V W
VW
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018920:Coculture Techniques; D053938:DNA Fragmentation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D039503:Integrin alpha6; D007797:Laminin / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D015703:Antigens, CD; D004791:Enzyme Inhibitors; D039503:Integrin alpha6; D007797:Laminin; D010770:Phosphotransferases