Macrophage Ontogeny and the Extracellular Matrix Contribute to Macrophage Activation in Aged Murine Livers

巨噬细胞个体发育和细胞外基质有助于衰老小鼠肝脏中巨噬细胞的激活

• 批准号: 9326625
• 负责人: Elizabeth Stahl
• 金额: $ 3.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326625
• 关键词: Address; Adoptive Transfer; Affect; Aging; Aging-Related Process; Biochemical; Biological Assay; Biology; Biomimetics; Bone Marrow; Cell Ontogeny; Cells; Characteristics; Collagen; Data; Dimensions; Disease; Elderly; Embryo; Endotoxins; Engineering; Environment; Extracellular Matrix; Fellowship; Fibrosis; Functional disorder; Glycoproteins; Growth; Hepatocyte; Homeostasis; ITGAM gene; Immune System Diseases; Immune System and Related Disorders; Immune Tolerance; Immune response; Immune system; Incidence; Individual; Infection; Infectious Agent; Inflammaging; Inflammation; Inflammatory; Injury; Kinetics; Kupffer Cells; Lead; Liver; Macrophage Activation; Maintenance; Malignant Neoplasms; Mechanics; Mentors; Mentorship; Modeling; Mus; Myocardium; National Research Service Awards; Normal tissue morphology; Organ; Phenotype; Play; Population; Property; Recruitment Activity; Regulation; Reporting; Research; Role; Scientist; Severities; Signal Transduction; Source; Surface; Techniques; Therapeutic Intervention; Tissues; Training; United States; Work; age effect; age group; age related; aged; career; chronic liver disease; healthy aging; implantation; in vivo; innovation; macrophage; novel therapeutics; outcome forecast; regenerative; repaired; response; scaffold; targeted treatment; therapeutic target; virtual; viscoelasticity

Abstract The liver is the most regenerative organ in the body following injury or insult, however it is unclear how some components of the liver, namely the extracellular matrix (ECM) and resident macrophages, interact and change with aging. Previous work has identified a significant age-related increase in the number and activation of liver-resident macrophages. Recent studies have also identified the existence of two distinct subsets of macrophages in the liver: Kupffer cells (embryonic origin) and bone marrow derived macrophages. No study to date has examined how these two macrophage subsets are affected by the aging process, which may have major implications for the ability of the host to maintain immune tolerance, as well as respond to infection, injury, and other chronic liver diseases. We hypothesize that the predominant population of liver macrophages will shift from embryonic derived to bone marrow derived macrophages in aged murine livers, with major implications for normal tissue functions. We also hypothesize that changes in the ECM, which composes the macrophage “niche”, will undergo an increase in stiffness and contribute to macrophage dysfunction with aging. To assess these hypotheses, we have devised two aims: to 1) examine the role of cell ontogeny on the observed increase in resident macrophage number and activation in the aged murine liver and 2) characterize the age-related changes in mechanical and biochemical composition of liver ECM and the effect on the liver-resident macrophages. Our innovative approach involves a transdisciplinary research and mentoring team including basic scientists and engineers using advanced models and techniques such as bone marrow chimeric mice, whole organ decellularization, and biomimetic scaffolds to address our research question. It is critically important to understand how liver macrophage phenotype and function as well as the liver ECM change during aging, and the reciprocal regulation between these two tissue components, to devise new therapies to reduce age-related inflammation and extend healthy aging.

摘要 肝脏是机体损伤或损伤后再生能力最强的器官，但目前尚不清楚如何再生。 肝脏的某些成分，即细胞外基质（ECM）和驻留的巨噬细胞，相互作用， 随着年龄的增长而变化。以前的工作已经确定了一个显着的年龄相关的数量和激活的增加 肝脏巨噬细胞的数量最近的研究还发现存在两个不同的亚群， 肝脏中的巨噬细胞：枯否细胞（胚胎来源）和骨髓来源的巨噬细胞。没有研究， date已经研究了这两种巨噬细胞亚群如何受到衰老过程的影响，这可能 对宿主维持免疫耐受性以及对感染，损伤， 和其他慢性肝病。我们假设主要的肝巨噬细胞群体将转移 从胚胎来源的巨噬细胞到骨髓来源的巨噬细胞，在老年小鼠肝脏中， 正常组织功能。我们还假设，细胞外基质的变化， “壁龛”，将经历刚度的增加，并有助于随着衰老的巨噬细胞功能障碍。评估 根据这些假设，我们设计了两个目标：1）检查细胞个体发育对观察到的增加的作用 在老年小鼠肝脏中的常驻巨噬细胞数量和活化方面，以及2）表征年龄相关的 肝脏ECM的机械和生化组成的变化以及对肝脏驻留的影响 巨噬细胞我们的创新方法涉及一个跨学科的研究和指导团队，包括基本的 科学家和工程师使用先进的模型和技术，如骨髓嵌合小鼠，整个 器官去细胞化和仿生支架来解决我们的研究问题。至关重要的是， 了解肝脏巨噬细胞表型和功能以及肝脏ECM在衰老过程中的变化， 这两种组织成分之间的相互调节，以设计新的治疗方法来减少与年龄相关的 炎症和延长健康衰老。