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

摘要 肝脏是人体在受到伤害或侮辱后最具再生能力的器官，但目前还不清楚是如何发生的。 肝脏的某些组成部分，即细胞外基质(ECM)和驻留巨噬细胞，相互作用和 随着年龄的增长而改变。先前的研究已经发现，与年龄相关的数量和激活显著增加 驻留在肝脏的巨噬细胞。最近的研究还发现，存在两个不同的子集 肝脏中的巨噬细胞：库普弗细胞(胚胎来源)和骨髓来源的巨噬细胞。没有研究要做 Date研究了这两个巨噬细胞亚群如何受到衰老过程的影响，这可能是 对宿主维持免疫耐受性以及对感染、损伤、 以及其他慢性肝病。我们假设，肝巨噬细胞的主要群体将发生转变 在老年小鼠肝脏中，从胚胎来源的巨噬细胞到骨髓来源的巨噬细胞，及其主要意义 组织功能正常。我们还假设组成巨噬细胞的细胞外基质发生变化 随着年龄的增长，“小生境”将经历僵硬的增加，并导致巨噬细胞功能障碍。评估 在这些假设下，我们设计了两个目的：1)检查细胞个体发育在观察到的增加中的作用 老年小鼠肝脏内滞留巨噬细胞的数量和激活以及2)与年龄相关的特征 肝细胞外基质机械成分和生化成分的变化及其对肝脏滞留的影响 巨噬细胞。我们的创新方法包括一个跨学科的研究和指导团队，包括Basic 科学家和工程师使用先进的模型和技术，如骨髓嵌合小鼠， 器官脱细胞和仿生支架来解决我们的研究问题。至关重要的是， 了解肝脏巨噬细胞的表型和功能以及肝脏细胞外基质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 发炎，延缓健康衰老。

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.