Liver sinusoidal endothelial cells and fibrosis.

描述（由申请人提供）：在体外，来自健康肝脏的肝窦内皮细胞（LSECs）可以阻止肝星状细胞（HSC）的激活，并促进活化的HSC的失活，但已经“毛细血管化”的LSECs则没有这种作用。毛细化，LSEC开孔的丧失，以及更有组织的基底膜在Disse空间的形成，发生在纤维化之前。在体内，停止纤维化损伤后毛细血管化的药理学逆转加速了HSC的失活和纤维化的消退，而在继续纤维化刺激时毛细血管化的逆转可防止肝硬化的进展。因此毛细血管化不仅发生在肝纤维化之前，而且对肝纤维化是允许的。的目标

DESCRIPTION (provided by applicant): In vitro, liver sinusoidal endothelial cells (LSECs) from healthy liver prevent hepatic stellate cell (HSC) activation and promote inactivation of activated HSC, but LSECs that have "capillarized" do not. Capillarization, the loss of LSEC fenestration and formation of a more organized basement membrane in the space of Disse, precedes fibrosis. In vivo, pharmacological reversal of capillarization after discontinuing a fibrotic insult accelerates inactivation of HSC and regression of fibrosis, whereas reversal of capillarization while a fibrotic stimulus is continued prevents progression of cirrhosis. Thus capillarization doesn't just precede fibrosis, but is permissive for hepatic fibrosis. The goals of this proposal are two-fold. First, examine how LSECs promote HSC quiescence. Second, elucidate the mechanisms that lead to capillarization. This proposal has three specific aims. In specific aim 1 the protein secreted by LSECs that promotes HSC quiescence will be identified, its in vivo activity will be confirmed, expression patterns within the liver will be immunolocalize, and its signaling within HSC will be examined. Specific 2 will examine the genesis of "capillarized" LSECs in a model of toxin-induced fibrosis and confirm that capillarized LSECs in a model of diet-induced non-alcoholic steatohepatitis have the same origin. Integrin expression, endocytosis and endocytosis receptors, and transcriptomic profiling in in vivo capillarized LSECs will be compared with LSECs from normal liver and in vitro capillarized LSECs to better understand capillarization. Preliminary data for specific aim 3 has identified a change within the fibrotic liver associated with loss of LSEC fenestration and with angiogenesis. Specific aim 3 will determine which type of liver cell is responsible for the change; confirm the association with loss of fenestration, HSC activation, fibrosis and angiogenesis; examine signaling pathways in the LSEC; and characterize the regulation of the change in the capillarized liver. Successful completion of these aims will transform our understanding of the mechanisms underlying capillarization and provide potential therapeutic targets to treat fibrosis.