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

• 批准号: 10319553
• 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
• 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/10319553
• 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; 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; Location; Metabolic syndrome; Minor; Modeling; Molecular; Normal Cell; 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; fatty liver disease; functional disability; in vivo; intrahepatic; liver injury; liver repair; mortality; non-alcoholic fatty liver disease; novel; novel strategies; novel therapeutic intervention; obese person; oxidized low density lipoprotein; prevent; progenitor; receptor mediated endocytosis; recruit; repaired; self-renewal; single-cell RNA sequencing; stem cell niche; stem cells; uptake

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.

项目摘要 目的1的假设是，肝窦内皮细胞（LSECs）的来源是常驻肝窦 在正常的更替过程中，常驻的干细胞驻留在一个促进其静止的干细胞龛中。目的 1将使用谱系跟踪来确定LSEC是否来自常驻的LSEC，将表征 LSEC和常驻细胞深入鉴定细胞分化标记物和谱系标记物，以确定 LSEC是否与其他肝细胞有共同的起源，将确定已知的信号通路， 已知的干细胞小生境配体，并将表征各种配体和细胞元件， 干细胞生态位 目的2的假设是代谢综合征特有的变化抑制了NO途径， LSEC并诱导毛细作用。这一目标将表征NAFLD在体外分离的LSEC中的信号传导 和离体分离自NAFLD的LSEC中。 目的3的假设是BM衍生的（“毛细血管化”）LSEC的内吞功能受损， 导致NAFLD中脂质的异常清除。目的3将检查取自以下组织的LSEC中脂质的摄取： 将使用活体多光子荧光共聚焦显微镜检查NAFLD大鼠的脂质摄取， 在NAFLD大鼠体内。干预将用于诱导BM衍生的LSEC成熟，研究将 检查这对脂质的体外和体内摄取的影响。最后，研究了诱导BM成熟的作用- 将衍生的LSEC对血清脂质水平的作用与他汀类药物的作用进行比较。 总的来说，这些目标将为我们理解肝脏中的居民胰岛素的作用提供重大进展。 生理学，这将是至关重要的未来的方法，以引起更大的贡献，从居民的健康， 修复肝损伤并驱动肝再生。这些研究也有可能揭示 导致NAFLD毛细血管化的机制，作为提供治疗策略以预防两种 毛细作用的后果：毛细作用对高脂血症的贡献和 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， 导致NAFLD中脂质水平升高，伴随心血管死亡风险增加， 这可能会导致新的方法来治疗这方面的高脂血症。