Physiologically, four major types of hepatic cells - the liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes - reside inside liver sinusoids and interact with flowing peripheral cells under blood flow. It is hard to mimic an in vivo liver sinusoid due to its complex multiple cell-cell interactions, spatiotemporal construction, and mechanical microenvironment. Here we developed an in vitro liver sinusoid chip by integrating the four types of primary murine hepatic cells into two adjacent fluid channels separated by a porous permeable membrane, replicating liver's key structures and configurations. Each type of cells was identified with its respective markers, and the assembled chip presented the liver-specific unique morphology of fenestration. The flow field in the liver chip was quantitatively analyzed by computational fluid dynamics simulations and particle tracking visualization tests. Intriguingly, co-culture and shear flow enhance albumin secretion independently or cooperatively, while shear flow alone enhances HGF production and CYP450 metabolism. Under lipopolysaccharide (LPS) stimulations, the hepatic cell co-culture facilitated neutrophil recruitment in the liver chip. Thus, this 3D-configured in vitro liver chip integrates the two key factors of shear flow and the four types of primary hepatic cells to replicate key structures, hepatic functions, and primary immune responses and provides a new in vitro model to investigate the short-duration hepatic cellular interactions under a microenvironment mimicking the physiology of a liver.
Leukocyte transendothelial migration is a key step in their recruitment to sites of inflammation. However, synergic regulation of endothelium-expressed selectins on leukocyte transmigration remains unclear. In this study, an in vitro model was developed to investigate the dynamic contributions of P- and E-selectin to polymorphonuclear neutrophil (PMN) transmigration under static conditions. Human umbilical vein endothelial cells (HUVECs) were treated with LPS for 4 or 12 h to induce different expression of selectins and intercellular adhesion molecule (ICAM)-1. PMN transmigration was increased significantly by LPS stimulation, which was higher on 4-h than on 12-h LPS-treated HUVECs. Blocking and competitive tests indicated that P-selectin engages PSGL-1 to activate β-integrin and initiate PMN transmigration within the first 15 min, whereas E-selectin engages CD44 to influence PMN transmigration after 15 min. P- and E-selectin-induced β-integrin activation is likely conducted through the spleen tyrosine kinase signaling pathway. Complicated complementary and competitive mechanisms are involved in the interaction of P-/E-selectins and their ligands to promote PMN transmigration. These results provide direct evidence of the distinct and dynamic contribution of P- and E-selectins in mediating PMN transmigration and give new insight into PMN interaction with the vessel wall.-Gong, Y., Zhang, Y., Feng, S., Liu, X., Lü, S., Long, M. Dynamic contributions of P- and E-selectins to β-integrin-induced neutrophil transmigration.
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