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This Article Free via Open Access: OA OA Full Text Full Text (PDF) Supplemental Data OA All Versions of this Article: 2008-0122v1 2008-0122v2 26/7/1673    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rampon, C. Articles by Couraud, P.-O. Search for Related Content PubMed PubMed Citation Articles by Rampon, C. Articles by Couraud, P.-O.

TISSUE-SPECIFIC STEM CELLS

Molecular Mechanism of Systemic Delivery of Neural Precursor Cells to the Brain: Assembly of Brain Endothelial Apical Cups and Control of Transmigration by CD44

^aInstitut Cochin, Université Paris Descartes, Paris, France;
^bU567 and
^dU546, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France;
^cCentre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France;
^eUniversité Pierre et Marie Curie-Paris6, UMRS 546, Paris, France;
^fAssistance Publique–Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Fédération de Neurologie, Paris, France

Key Words. Neural precursor cells • Migration • Blood-brain barrier • CD44

Correspondence: Dr. Pierre Olivier Couraud, Ph.D., Institut Cochin UMR CNRS 8104/INSERM U 567, Département de Biologie Cellulaire, 22 rue Méchain, 75014, Paris, France. Telephone: (33)1 40 51 64 57; Fax: (33)1 40 51 64 73; e-mail: pierre-olivier.couraud{at}inserm.fr

Received February 8, 2008; accepted for publication March 31, 2008.
First published online in STEM CELLS EXPRESS   May 1, 2008.

Systemically injected neural precursor cells (NPCs) were unexpectedly shown to reach the cerebral parenchyma and induce recovery in various diffuse brain pathologies, including animal models of multiple sclerosis. However, the molecular mechanisms supporting NPC migration across brain endothelium remain elusive. Brain endothelium constitutes the blood-brain barrier, which uniquely controls the access of drugs and trafficking of cells, including leukocytes, from the blood to the brain. Taking advantage of the availability of in vitro models of human and rat blood-brain barrier developed in our laboratory and validated by us and others, we show here that soluble hyaluronic acid, the major ligand of the adhesion molecule CD44, as well as anti-CD44 blocking antibodies, largely prevents NPC adhesion to and migration across brain endothelium in inflammatory conditions. We present further evidence that NPCs, surprisingly, induce the formation of apical cups at the surface of brain endothelial cells, enriched in CD44 and other adhesion molecules, thus hijacking the endothelial signaling recently shown to be involved in leukocyte extravasation. These results demonstrate the pivotal role of CD44 in the trans-endothelial migration of NPCs across brain endothelial cells: we propose that they may help design new strategies for the delivery of therapeutic NPCs to the brain by systemic administration.

Disclosure of potential conflicts of interest is found at the end of this article.