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

肝窦内皮细胞祖细胞 (sprocs) 与慢性肝病

基本信息

批准号：
9884512
负责人：
LAURIE D DELEVE
金额：
$ 37.13万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884512
关键词：
Acute Advanced Glycosylation End Products Blood Blood Circulation Bone Marrow Cardiovascular Diseases Cell Differentiation process Cell Maturation Cells Cerebrovascular Disorders Cirrhosis Confocal Microscopy Cytometry Data Development Diabetes Mellitus Differentiation Antigens Elements Endothelial Cells Exposure to Expression Profiling Fatty Liver Fibrosis Fluorescence Future Goals Hepatic Stellate Cell Hepatocyte Hyperlipidemia Immunohistochemistry Impairment In Situ Hybridization In Vitro Injury Intervention Lead Ligands Lipids Liver Liver Regeneration Liver diseases Location Metabolic syndrome Minor Modeling Molecular Normal Cell Obesity Partial Hepatectomy Pathologic Processes Pathway interactions Patients Phenotype Physiological Physiology Play Population Proteins Proteomics Rattus Risk Role Serum Signal Pathway Signal Transduction Source Stream Therapeutic Thioacetamide Tissues cardiovascular risk factor cell type cerebrovascular chronic liver disease chronic liver injury endothelial stem cell functional disability in vivo intrahepatic liver injury liver repair mortality non-alcoholic fatty liver disease novel novel strategies novel therapeutic intervention oxidized low density lipoprotein prevent progenitor receptor mediated endocytosis recruit repaired self-renewal single-cell RNA sequencing stem cell niche stem cells uptake

项目摘要

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.

项目概要目标 1 的假设是常驻存储细胞是肝窦内皮细胞 (LSEC) 的来源在正常周转期间，常驻存储体驻留在促进其静止的干细胞生态位中。 1 将使用谱系追踪来确定 LSEC 是否源自常驻存储过程，将表征 LSEC和常驻sprocs深入识别细胞分化标记物和谱系标记物以确定 LSEC 是否与其他肝细胞具有共同起源，将识别已知的响应信号通路已知的干细胞生态位配体，并将表征组成的各种配体和细胞元件 sprocs 的干细胞生态位。目标 2 的假设是代谢综合征特有的变化抑制了 NO 通路 LSEC 并诱导毛细血管化该目标将表征体外分离的 LSEC 中 NAFLD 的信号传导。以及从 NAFLD 离体分离的 LSEC 中。目标 3 的假设是 BM 来源（“毛细血管化”）LSEC 的内吞功能受损导致 NAFLD 中脂质清除异常。目标 3 将检查取自 LSEC 的脂质摄取情况。患有 NAFLD 的大鼠将使用活体多光子荧光共聚焦显微镜检查脂质摄取患有 NAFLD 的大鼠体内的干预措施将用于诱导 BM 衍生的 LSEC 的成熟，并将进行研究。检查这对体外和体内脂质摄取的影响，最后是诱导 BM- 成熟的影响。衍生的 LSEC 对血清脂质水平的影响将与他汀类药物的效果进行比较。总的来说，这些目标将为我们理解常驻存储在肝脏中的作用提供重大进展。生理学，这对于未来的方法至关重要，以期从常驻存储过程中获得更大的贡献修复肝损伤并驱动肝再生。这些研究还有可能揭示这一点。导致 NAFLD 毛细血管化的机制作为提供预防两种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以及丧失最后，这些研究应该揭示一个重要的机制：导致 NAFLD 中血脂水平升高，并随之增加心血管死亡风险和这可能会导致治疗高脂血症这一方面的新方法。