Involvement of aquaporin-4 in astroglial cell migration and glial scar formation.
Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18+/-2 vs 58+/-4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 microm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25+/-4% migrated cells) in wild-type astroglia after approximately 90% reduction in aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.
Saadoun
Samira
S
Department of Medicine, Cardiovascular Research Institute, University of California, 505 Parnassus Avenue, San Francisco, CA 94143-0521, USA.
Papadopoulos
Marios C
MC
Watanabe
Hiroyuki
H
Yan
Donghong
D
Manley
Geoffrey T
GT
Verkman
A S
AS
D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002921:Cicatrix / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009995:Osmosis
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4