000146682 001__ 146682
000146682 005__ 20180317093148.0
000146682 0247_ $$2doi$$a10.5075/epfl-thesis-4666
000146682 02470 $$2urn$$aurn:nbn:ch:bel-epfl-thesis4666-4
000146682 02471 $$2nebis$$a5981535
000146682 037__ $$aTHESIS_LIB
000146682 041__ $$aeng
000146682 088__ $$a4666
000146682 245__ $$aBiophysical Regulation of Lymphatic Vessel Function$$bFlow as a Mediator of Immune Cell and Fluid Transport
000146682 269__ $$a2010
000146682 260__ $$aLausanne$$bEPFL$$c2010
000146682 300__ $$a145
000146682 336__ $$aTheses
000146682 520__ $$aLymphatic capillaries collect interstitial fluid and       dendritic cells from the periphery and deliver them to the       lymph nodes for immune surveillance and tolerance       maintenance. Upon injury and inflammation, lymphatic drainage       can increase rapidly, and thus the lymphatic capillaries       experience a broad range of fluid stresses and need to       respond rapidly to such changes. Our understanding of their       functional biology, adaptive ability and response to       pathological changes in the biophysical environment is still       very limited. This thesis focuses on how the lymphatic       capillary endothelium senses and responds to changes of its       biophysical environment with respect to its function,       including fluid and cell transport, in the context of       physiological and pathophysiological conditions. Using in vitro and in vivo models, we       demonstrate that lymphatic endothelium is exquisitely       sensitive to transmural flow, modulating both fluid and cell       transport functions even in the absence of inflammatory       cytokines. Flow increased lymphatic permeability and       dendritic cell (DC) transmigration, which were coincident       with changes in gene and protein expression of factor known       to be involved in these, including chemoattractant       chemokines, adhesion molecules and junctional proteins. These       data provide the first evidence that lymphatic endothelium       can regulate its transport functions in response to flow       cues. They also show for the first time that transmural flow       can, in the absence of inflammatory cues like TNF-a, drive       expression of DC adhesion molecules like ICAM-1 and       chemokines like CCL21 by lymphatic endothelium. Based on       these findings we suggest that lymphatic flow is an important       mediator of lymphatic function, particularly with respect to       DC recruitment and trafficking to the lymph node. Furthermore, the response of the lymphatic endothelium to       flow may be specific to the type of low, as lymphatic       endothelial cells (LECs) might react differently to luminal       shear flow, at physiological and pathophysiological levels,       compared to transmural flow. To address this we used laminar       shear stress chambers to expose only the apical surface of       the lymphatic endothelial cells (LECs) to shear stress and       demonstrated that lymphatic endothelium is indeed sensitive       to luminal flow, fine-tuning its expression of adhesion       molecules to modulate DC adhesion according to the shear       stress. Specifically, at extremely low shear, adhesion was       enhanced, unlike at higher shear, adhesion was downregulated.       This is consistent with the notion that DC adhesion to LECs       is only needed for entry but not transport in conducting       vessels, since only the absorbing capillaries have low shear       stresses. The interactions between DCs and LECs were strongly       mediated by CCL21 and its receptor CCR7. These findings       suggest that luminal shear stress acts as an active       mechanosignal in LECs to potentially facilitate the traffic       of immune cells inside of the lymphatic vessel to reach the       lymph node and trigger an immune response. Additionally, we demonstrated that lymphatic vessels       respond differentially to immunogenic and tolerogenic       inflammatory stimulus. We used in vitro models to       evaluate lymphatic uptake and lymphatic participation in       dendritic cell transmigration in the presence of various       inflammatory stimuli. We found that lymphatic endothelium       exposed to TNF-a or complement activation were more       conductive to dendritic cell transmigration, while LPS and       TGF-β had opposite effect, affecting DCs to decrease DC       transmigration. We further presented some insights in       similarities in tumor and dendritic cells intravasation into       inflamed lymphatic capillaries. These findings imply that       lymphatic activation and participation in immune cells       transport is not a universal phenomenon, but is strongly       dependent on the nature of the inflammation. In conclusion, this work highlights the critical role of       biophysical environment in lymphatic endothelial function,       and how exquisitely sensitive the lymphatic capillaries are       to their extracellular environment and how they use multiple       cues to sense inflammation and danger, modulating their       transport functions accordingly to regulate the delivery of       antigens and immune cells to the lymph nodes.
000146682 6531_ $$alymphatic endothelium
000146682 6531_ $$ainterstitial flow
000146682 6531_ $$ashear stress
000146682 6531_ $$ainflammation
000146682 6531_ $$adendritic cells
000146682 6531_ $$aCCL21
000146682 6531_ $$aCCR7
000146682 6531_ $$aendothélium lymphatique
000146682 6531_ $$aflux interstitiel
000146682 6531_ $$aforces de cisaillements
000146682 6531_ $$astress
000146682 6531_ $$ainflammation
000146682 6531_ $$acellules dendritiques
000146682 6531_ $$aCCL21
000146682 6531_ $$aCCR7
000146682 700__ $$aMiteva, Dimana
000146682 720_2 $$0242992$$aSwartz, Melody$$edir.$$g160091
000146682 8564_ $$s8345417$$uhttps://infoscience.epfl.ch/record/146682/files/EPFL_TH4666.pdf$$yTexte intégral / Full text$$zTexte intégral / Full text
000146682 909CO $$ooai:infoscience.tind.io:146682$$pthesis-bn2018$$pthesis
000146682 909C0 $$0252115$$pLLCB$$xU11747
000146682 918__ $$aSV$$cIBI-SV$$dEDBB
000146682 919__ $$aLMBM
000146682 920__ $$b2010
000146682 970__ $$a4666/THESES
000146682 973__ $$aEPFL$$sPUBLISHED
000146682 980__ $$aTHESIS