van Buul Jaap D, Voermans Carlijn, van den Berg Veronique, Anthony Eloise C, Mul Frederik P J, van Wetering Sandra, van der Schoot C Ellen, Hordijk Peter L
Department of Experimental Immunohematology, CLB and Laboratory for Experimental and Clinical Immunology, and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Immunol. 2002 Jan 15;168(2):588-96. doi: 10.4049/jimmunol.168.2.588.
The success of stem cell transplantation depends on the ability of i.v. infused stem cells to engraft the bone marrow, a process referred to as homing. Efficient homing requires migration of CD34(+) cells across the bone marrow endothelium, most likely through the intercellular junctions. In this study, we show that loss of vascular endothelial (VE)-cadherin-mediated endothelial cell-cell adhesion increases the permeability of monolayers of human bone marrow endothelial cells (HBMECs) and stimulates the transendothelial migration of CD34(+) cells in response to stromal cell-derived factor-1alpha. Stromal cell-derived factor-1alpha-induced migration was dependent on VCAM-1 and ICAM-1, even in the absence of VE-cadherin function. Cross-linking of ICAM-1 to mimic the leukocyte-endothelium interaction induced actin stress fiber formation but did not induce loss of endothelial integrity, whereas cross-linking of VCAM-1 increased the HBMEC permeability and induced gaps in the monolayer. In addition, VCAM-1-mediated gap formation in HBMEC was accompanied by and dependent on the production of reactive oxygen species. These data suggest that modulation of VE-cadherin function directly affects the efficiency of transendothelial migration of CD34(+) cells and that activation of ICAM-1 and, in particular, VCAM-1 plays an important role in this process through reorganization of the endothelial actin cytoskeleton and by modulating the integrity of the bone marrow endothelium through the production of reactive oxygen species.
干细胞移植的成功取决于静脉输注的干细胞植入骨髓的能力，这一过程称为归巢。高效归巢需要CD34(+)细胞穿过骨髓内皮迁移，最有可能是通过细胞间连接。在本研究中，我们发现血管内皮（VE）-钙黏蛋白介导的内皮细胞-细胞黏附丧失会增加人骨髓内皮细胞（HBMEC）单层的通透性，并刺激CD34(+)细胞对基质细胞衍生因子-1α的跨内皮迁移。基质细胞衍生因子-1α诱导的迁移依赖于VCAM-1和ICAM-1，即使在缺乏VE-钙黏蛋白功能的情况下也是如此。ICAM-1交联以模拟白细胞-内皮相互作用可诱导肌动蛋白应激纤维形成，但不会导致内皮完整性丧失，而VCAM-1交联会增加HBMEC通透性并在单层中诱导间隙形成。此外，HBMEC中VCAM-1介导的间隙形成伴随着活性氧的产生并依赖于活性氧的产生。这些数据表明，VE-钙黏蛋白功能的调节直接影响CD34(+)细胞跨内皮迁移的效率，并且ICAM-1尤其是VCAM-1的激活通过内皮肌动蛋白细胞骨架的重组以及通过活性氧的产生调节骨髓内皮的完整性在这一过程中起重要作用。
