Molecular mechanism of systemic delivery of neural precursor cells to the brain: Assembly of brain endothelial apical cups and control of transmigration by CD44
Molecular mechanism of systemic delivery of neural precursor cells to the brain: Assembly of brain endothelial apical cups and control of transmigration by CD44
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DOI：
10.1634/stemcells.2008-0122
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Couraud, Pierre-Olivier
中科院分区：
文献类型：
--
作者：
Rampon, Christine;Weiss, Nicolas;Couraud, Pierre-Olivier
全身注射的神经前体细胞（NPC）出乎意料地显示出到达脑实质，并诱导各种弥漫性脑病变，包括多发性硬化症的动物模型的恢复。然而，支持NPC跨脑内皮迁移的分子机制仍然难以捉摸。脑内皮构成血脑屏障，其独特地控制药物的进入和细胞（包括白细胞）从血液到脑的运输。利用我们实验室开发的人和大鼠血脑屏障体外模型的可用性，并由我们和其他人验证，我们在这里表明，可溶性透明质酸，粘附分子CD44的主要配体，以及抗CD44阻断抗体，在很大程度上防止NPC粘附和迁移在炎症条件下穿过脑内皮。我们提出了进一步的证据表明，NPC，令人惊讶的是，诱导在脑内皮细胞表面的顶杯的形成，富含CD44和其他粘附分子，从而劫持内皮信号最近被证明参与白细胞外渗。这些结果表明，CD44在跨脑内皮细胞的NPC的跨内皮迁移的关键作用：我们建议，他们可能有助于设计新的策略，通过全身给药的治疗NPC的大脑。
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.