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

¹ Institut Cochin, Université Paris Descartes, Paris 75014, France; INSERM, U567, Paris 75014, France; CNRS, UMR 8104, Paris 75014, France
² INSERM U546, Paris 75013, France; Université Pierre et Marie Curie-Paris6, UMRS 546, Paris 75005, France
³ INSERM U546, Paris 75013, France; Université Pierre et Marie Curie-Paris6, UMRS 546, Paris 75005, France; Assistance Publique – Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Fédération de Neurologie, Paris 75651, France

^* To whom correspondence should be addressed. E-mail: couraud{at}cochin.inserm.fr.

	Abstract

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 prevent NPC adhesion to and migration across brain endothelium in inflammatory conditions. We present further evidence that NPCs surprinsingly 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.