Molecular Mechanism of Systemic Delivery of Neural Precursor Cells to the Brain

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Previously Highlighted Papers - 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

Christine Rampon^a^,b^,c, Nicolas Weiss^a^,b^,c, Cyrille Deboux^d^,e, Nathalie Chaverot^a^,b^,c, Florence Miller^a^,b^,c, Delphine Buchet^d^,e, Hélène Tricoire-Leignel^a^,b^,c, Sylvie Cazaubon^a^,b^,c, Anne Baron-Van Evercooren^d^,e^,f, Pierre-Olivier Couraud^a^,b^,c

ABSTRACT

Systemically injected neural precursor cells (NPCs) were unexpectedlyshown to reach the cerebral parenchyma and induce recovery invarious diffuse brain pathologies, including animal models ofmultiple sclerosis. However, the molecular mechanisms supportingNPC migration across brain endothelium remain elusive. Brainendothelium constitutes the blood-brain barrier, which uniquelycontrols the access of drugs and trafficking of cells, includingleukocytes, from the blood to the brain. Taking advantage ofthe availability of In Vitro models of human and rat blood-brainbarrier developed in our laboratory and validated by us andothers, we show here that soluble hyaluronic acid, the majorligand of the adhesion molecule CD44, as well as anti-CD44 blockingantibodies, largely prevents NPC adhesion to and migration acrossbrain endothelium in inflammatory conditions. We present furtherevidence that NPCs, surprisingly, induce the formation of apicalcups at the surface of brain endothelial cells, enriched inCD44 and other adhesion molecules, thus hijacking the endothelialsignaling recently shown to be involved in leukocyte extravasation.These results demonstrate the pivotal role of CD44 in the trans-endothelialmigration of NPCs across brain endothelial cells: we proposethat they may help design new strategies for the delivery oftherapeutic NPCs to the brain by systemic administration.