Liver Sinusoidal Endothelial Cell Progenitor Cells (sprocs) and Chronic Liver Disease

项目总结 目标1的假设是驻留链状细胞是肝窦内皮细胞(Lsecs)的来源。 在正常周转期间，驻留的链状细胞驻留在促进其静止的干细胞利基中。目标 1将使用谱系跟踪来确定LSEC是否源自驻留的sprc，将表征 LSECs和常驻spros深入识别细胞分化标记和谱系标记，以确定 LSEC是否与其他肝细胞有共同的起源，将识别已知的反应信号通路 到已知的干细胞利基配体，并将表征组成的各种配体和细胞元件 链状细胞的干细胞利基。 Aim 2的假设是，代谢综合征特有的变化抑制了体内的NO途径 LSECs，诱导毛细血管形成。本研究的目的是研究体外分离的LSEC中NAFLD的信号特征。 体外分离的非酒精性脂肪肝LSECs。 目标3的假设是骨髓来源的(“毛细血管”)LSECs的内吞功能受损 有助于NAFLD中脂质的异常清除。目标3将检查LSECs对来自 并将使用活体多光子荧光共聚焦显微镜检查大鼠对脂肪的摄取 在非酒精性脂肪肝大鼠体内。干预措施将用于诱导骨髓来源的LSEC成熟，研究将 检查这对体外和体内脂质摄取的影响。诱导BM成熟的效果。 将衍生的LSECs与他汀类药物对血脂水平的影响进行比较。 总而言之，这些目标将大大提高我们对驻留链球蛋白在肝脏中的作用的理解。 生理学，这对于未来的方法将是至关重要的，以促使常驻spros对 修复肝脏损伤，促进肝脏再生。这些研究还有可能揭示 导致NAFLD毛细血管形成的机制是提供预防两种疾病的治疗策略的前奏 毛细血管化的后果：毛细血管化对高脂血症的贡献和丧失 抑制肝星状细胞活化。最后，这些研究应该揭示一个重要的机制，即 导致NAFLD的血脂水平升高，并伴随着心血管死亡风险的增加和 这可能导致治疗这一方面的高脂血症的新方法。

PROJECT SUMMARY The hypothesis for aim 1 is that resident sprocs are the source of liver sinusoidal endothelial cells (LSECs) during normal turnover and that resident sprocs reside in a stem cell niche that promotes their quiescence. Aim 1 will use lineage-tracing to determine whether LSECs are derived from resident sprocs, will characterize LSECs and resident sprocs in-depth to identify cell differentiation markers and lineage markers to determine whether LSECs share common origins with other liver cells, will identify signaling pathways known to respond to known stem cell niche ligands, and will characterize the various ligands and cellular elements that compose the stem cell niche for sprocs. The hypothesis for aim 2 is that changes particular to the metabolic syndrome suppress the NO pathway in LSECs and induce capillarization. This aim will characterize the signaling in NAFLD in isolated LSECs in vitro and in LSECs isolated from NAFLD ex vivo. The hypothesis for aim 3 is that the impaired endocytotic function of BM-derived (“capillarized”) LSECs contributes to aberrant clearance of lipids in NAFLD. Aim 3 will examine uptake of lipids in LSECs taken from rats with NAFLD and will use intravital multiphoton fluorescence confocal microscopy to examine lipid uptake in vivo in rats with NAFLD. Interventions will be used to induce maturation of BM-derived LSECs and studies will examine the effect of this on in vitro and in vivo uptake of lipid. Finally the effect of inducing maturation of BM- derived LSECs on serum lipid level will be compared with the effect of a statin. Collectively, these aims will provide a major advance in our understanding of the role of resident sprocs in liver physiology, which will be critical for future approaches to elicit a greater contribution from resident sprocs to the repair of liver injury and to drive liver regeneration. These studies also have the potential to uncover the mechanisms leading to capillarization in NAFLD as a prelude to providing therapeutic strategies to prevent two consequences of capillarization: the contribution of capillarization to hyperlipidemia and the loss of the ability to suppress hepatic stellate cell activation. Finally, these studies should uncover an important mechanism that contributes to elevated lipid levels in NAFLD with its attendant increased risk of cardiovascular mortality and that may lead to novel approaches to treat this aspect of hyperlipidemia.