NCAM Polysialylation Enhances the Sensitivity of ES Cell-derived Neural Precursors to Migration Guidance Cues

¹ Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, Bonn, Germany
² Unité de Neurovirologie et Régénération du Système Nerveux, Institut Pasteur, Paris, France
³ Institute of Neuroimmunology, Charité, Humboldt University of Berlin

^* To whom correspondence should be addressed. E-mail: brustle{at}uni-bonn.de.

	Abstract

The development of stem cell-based neural repair strategies requires detailed knowledge on the interaction of migrating donor cells with the host brain environment. Here we report that overexpression of polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), in ES cell-derived glial precursors (ESGPs) strikingly modifies their migration behavior in response to guidance cues. ESGPs transduced with a retrovirus encoding the polysialyltransferase STX exhibit enhanced migration in monolayer cultures and an increased penetration of organotypic slice cultures. Chemotaxis assays show that overexpression of PSA results in an enhanced chemotactic migration towards gradients of a variety of chemoattractants including fibroblast growth factor 2 (FGF2), platelet-derived growth factor (PDGF) and brain-derived neurotrophic factor (BDNF), and that this effect is mediated via the phosphatidylinositol 3'-kinase (PI3K) pathway. Moreover, PSA-overexpressing ESGPs also exhibit an enhanced chemotactic response to tissue explants derived from different brain regions. The effect of polysialylation on directional migration is preserved in vivo. Upon transplantation into the adult striatum, PSA-overexpressing, but not control cells display a targeted migration towards the subventricular zone. Based on these data we propose that PSA plays a crucial role in modulating the ability of migrating precursor cells to respond to regional guidance cues within the brain tissue.

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