Abstract
We developed a microfluidic model of microcirculation containing both blood and lymphatic vessels for examining vascular permeability. The designed microfluidic device harbors upper and lower channels that are partly aligned and are separated by a porous membrane, and on this membrane, blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs) were cocultured back-to-back. At cell-cell junctions of both BECs and LECs, claudin-5 and VE-cadherin were detected. The permeability coefficient measured here was lower than the value reported for isolated mammalian venules. Moreover, our results showed that the flow culture established in the device promoted the formation of endothelial cell-cell junctions, and that treatment with histamine, an inflammation-promoting substance, induced changes in the localization of tight and adherens junction-associated proteins and an increase in vascular permeability in the microdevice. These findings indicated that both BECs and LECs appeared to retain their functions in the microfluidic coculture platform. Using this microcirculation device, the vascular damage induced by habu snake venom was successfully assayed, and the assay time was reduced from 24 h to 30 min. This is the first report of a microcirculation model in which BECs and LECs were cocultured. Because the micromodel includes lymphatic vessels in addition to blood vessels, the model can be used to evaluate both vascular permeability and lymphatic return rate.
Highlights
Microcirculation plays a crucial role in the supply of oxygen and nutrients from the blood to extravascular tissues
We focused the interaction between blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs), and in the newly developed device, the flow conditions mimicked vascular and lymphatic flow and molecules moved from blood vessels to lymphatic vessels through an extracellular matrix (ECM) hydrogel
Stimulation with 100 mM histamine completely disrupted cell-cell contacts in both BECs and LECs cultured in wells. These results indicated that VEcadherin and claudin-5 were not prominently localized at cell-cell junctions in cells cultured in wells, and cell-cell contacts were readily disrupted following histamine stimulation
Summary
Microcirculation plays a crucial role in the supply of oxygen and nutrients from the blood to extravascular tissues. The microcirculation system consists of blood and lymphatic vascular capillaries and the interstitium, and functional disorders of the microcirculation system are strongly related to, for example, inflammatory responses, swelling, and tumor. Microcirculation-on-a-Chip www.jsps.go.jp/english/e-grants/grants01.html), and the Core Research for Evolutional Science and Technology (JST, CREST) Program (to Kae S, http:// www.jst.go.jp/kisoken/crest/en/)
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