Human mast cell progenitors use α4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions

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Abstract
Mast cells (MCs) are central to asthma and other allergic diseases, and for responses to infection and tissue injuries. MCs arise from committed progenitors (PrMCs) that migrate from the circulation to tissues by incompletely characterized mechanisms, and differentiate in situ in perivascular connective tissues of multiple organs. PrMCs derived in vitro from human cord blood were examined for adhesion molecule expression and their ability to adhere to human umbilical vein endothelial cells (HUVECs) under conditions that mimic physiologic shear flow. The PrMCs expressed α4β1, low levels of β7, and the β2-integrins αLβ2 and αMβ2. The PrMCs also expressed PSGL-1, but not L-selectin. At low (0.5 dynes/cm2-1.0 dynes/cm2) shear stress, PrMCs attached and rolled on recombinant E-selectin and P-selectin and VCAM-1. An anti–PSGL-1 monoclonal antibody (mAb) blocked essentially all adhesion to P-selectin but reduced adhesion to E-selectin by only 40%, suggesting PrMCs express other ligands for E-selectin. PrMCs adhered strongly to tumor necrosis factor-α (TNF-α)–activated HUVECs, whereas adhesion to interleukin 4 (IL-4)–activated HUVECs was lower. PrMC adhesion to IL-4–activated HUVECs was totally α4-integrin– and VCAM-1–dependent. Adhesion to TNF-α–activated HUVECs was blocked by 50% by mAbs against α4-integrin, vascular cell adhesion molecule–1 (VCAM-1), E-selectin, or PSGL-1, whereas combinations of mAbs to α4-integrin plus PSGL-1, or VCAM-1 plus E-selectin, blocked adhesion by greater than 70%. Thus, PrMCs derived in vitro predominantly use α4-integrin, VCAM-1, PSGL-1, and other ligands that bind E-selectin for adhesion to cytokine-activated HUVEC monolayers. These observations may explain the abundance of MCs at sites of mucosal inflammation, where VCAM-1 and E-selectin are important inducible receptors.

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