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Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury

Kurtis I. Auguste^*,, Songwan Jin^*, Kazunori Uchida, Donghong Yan, Geoffrey T. Manley, Marios C. Papadopoulos^*, and A. S. Verkman^*

Departments of
^* Medicine and Physiology, and

Neurological Surgery, University of California, San Francisco, California, USA; and

Academic Neurosurgery Unit, St. George’s University of London, London, UK

¹Correspondence: 1246 Health Sciences East Tower, University of California, San Francisco, 505 Parnassus Ave., San Francisco, CA 94143-0521, USA. E-mail: alan.verkman{at}ucsf.edu

We reported previously that astroglia cultured from aquaporin-4-deficient (AQP4^–/–) mice migrate more slowly in vitro than those from wild-type (AQP4^+/+) mice (J. Cell Sci. 2005;118, 5691–5698). Here, we investigate the migration of fluorescently labeled AQP4^+/+ and AQP4^–/– astroglia after implantation into mouse brains in which directional movement was stimulated by a planar stab wound 3 mm away from the axis of the injection needle. Two days after cell injection we determined the location, elongation ratio, and orientation of labeled cells. Migration of AQP4^+/+ but not AQP4^–/– cells toward the stab was greater than away from the stab. AQP4^+/+ astroglia moved on average 1.5 mm toward the stab compared with 0.6 mm for AQP4^–/– cells. More than 25% of the migrating AQP4^+/+ cells but <3% of AQP4^–/– cells appeared elongated (axial ratio>2.5). In transwell assays, AQP4^+/+ astroglia migrated faster than AQP4^–/– cells in a manner dependent on pore size. At 8 h, 50% of AQP4^+/+ cells migrated through 8-µm diameter pores, whereas equivalent migration of AQP4^–/– cells was found for 12-µm diameter pores. These results provide in vivo evidence for AQP4-dependent astroglial migration and suggest that modulation of AQP4 expression or function might alter glial scarring—Auguste, K. I., Jin S., Uchida K., Yan D., Manley G. T., Papadopoulos M. C., Verkman A. S. Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury.

Key Words: AQP4 • astrocyte • chemotaxis • reactive gliosis • water channel

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