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Efferocytosis by Bone Marrow Stromal Cells and Bone Aging

骨髓基质细胞的胞吞作用和骨老化

基本信息

批准号：
10430637
负责人：
Laura M Calvi
金额：
$ 46.2万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10430637
关键词：
AMD3100 Address Adult Aging Apoptotic BAI1 gene Biology Bone Marrow Bone marrow failure Breast CXCL1 gene CXCL12 gene CXCR4 gene Cell Aging Cells Chronic Chronic Obstructive Pulmonary Disease Clinical Clinical Trials Data Degenerative Disorder Development Disease Dose Flow Cytometry Functional disorder Genetic Models Genetic Recombination Genetic Transcription Goals Health Homeostasis Human IL8RB gene Immune Impairment In Vitro Inflammation Inflammatory Insulin-Like Growth Factor I Interleukin-1 Interleukin-1 beta Knowledge Label Longevity Maintenance Measures Mediating Mesenchymal Metabolic Metals Mission Mitochondria Modeling Molecular Mus Oxidative Phosphorylation Oxidative Stress Pancreas Pathogenicity Pathologic Phagocytes Phagocytosis Pharmacology Phenotype Physiology Population Process Public Health RNA Reactive Oxygen Species Reporting Role Signal Transduction Skeleton Stromal Cells Tamoxifen Testing Transgenic Organisms United States National Institutes of Health age related aged antioxidant enzyme base biomechanical test bone bone aging bone health bone loss bone repair bone turnover catalase disability drug repurposing improved in vivo inhibitor innovation loss of function macrophage mesenchymal stromal cell mitochondrial dysfunction mouse model neutrophil novel novel therapeutics osteoblast differentiation osteogenic osteoimmunology overexpression particle pathogen preclinical study prevent receptor senescence serine receptor skeletal stem stem cells

项目摘要

Efferocytosis by bone marrow stromal cells and bone aging Pre-clinical studies show that senescent bone marrow-derived mesenchymal stromal (a.k.a. stem) cells (MSCs) and osteolineage cells contribute to age-dependent bone loss and bone marrow failure. Therefore, the identification of novel mechanisms that accelerate MSC dysfunction could enable mechanistic approaches to degenerative processes that impact the skeleton. While a handful of in vitro studies previously demonstrated MSCs’ ability to phagocytose apoptotic cells (efferocytosis), matrix, pathogens and metal particles, whether efferocytosis by MSCs impacts their function and bone maintenance is not known. We found that bone marrow MSCs indeed efferocytose apoptotic neutrophils in vivo. Preliminary data from adult mice with transgenic overexpression of the direct phosphatidyl serine receptor BAI1 in MSCs suggest that chronic low dose enhancement of efferocytosis by MSCs may be beneficial to skeletal health. We also found that, in aged mice, efferocytosis by MSCs is significantly increased. Moreover, transcriptional and functional preliminary data in vitro suggest that excessive efferocytosis by MSCs decreases osteoblastic differentiation and promotes senescence. Since efferocytosis is accompanied by oxidative stress and mitochondrial changes, which we previously found to modulate osteoblastic differentiation, mitochondrial disruption may mediate functional changes in MSCs that clear high numbers of apoptotic cells. Based on these data, we hypothesize that phagocytosis by MSCs is an important component of osteoimmunology; however when pathologically increased in aging, it causes MSC oxidative stress, mitochondrial dysfunction and senescence, thus contributing to bone loss. To test this, using aging and genetic models, we will 1) determine the mechanism of MSC efferocytosis; 2) define the pathogenic mechanisms induced by efferocytosis in MSCs; and 3) establish the role of efferocytosis by MSCs in normal osteoimmunology and in aged bone. Defining the role of facultative phagocytosis/efferocytosis in metabolic changes and senescence in MSC and their relevance to human aging and disease will provide innovative, actionable strategies impacting degenerative disorders that target the skeleton.

骨髓基质细胞胞饮作用与骨老化临床前研究表明，衰老的骨髓来源的间充质基质（a.k.a.干细胞并且骨系细胞导致年龄依赖性骨丢失和骨髓衰竭。因此鉴定加速MSC功能障碍的新机制可以使机械方法影响骨骼的退化过程虽然之前的一些体外研究表明， MSC吞噬凋亡细胞（细胞吞噬）、基质、病原体和金属颗粒的能力， MSC的巨噬细胞影响其功能，骨维持尚不清楚。我们发现骨髓骨髓间充质干细胞在体内确实能促进凋亡的中性粒细胞。来自具有转基因的成年小鼠的初步数据 MSC中直接磷脂酰丝氨酸受体BAI 1的过度表达表明，慢性低剂量骨髓间充质干细胞增强细胞发热作用可能有利于骨骼健康。我们还发现，在老年小鼠中， MSC的细胞增殖显著增加。此外，体外转录和功能的初步数据表明MSC过度的细胞增殖减少了成骨细胞的分化并促进衰老。由于红细胞增多症伴随着氧化应激和线粒体的变化，为了调节成骨细胞的分化，线粒体破坏可能介导MSC的功能变化，清除大量凋亡细胞。基于这些数据，我们假设MSC的吞噬作用是一种免疫调节机制。骨免疫学的重要组成部分;然而，当在衰老中病理性增加时，它导致MSC 氧化应激、线粒体功能障碍和衰老，从而导致骨丢失。为了测试这一点，使用衰老和遗传模型，我们将1）确定MSC红细胞增多症的机制; 2）确定致病性在MSC中由细胞增殖诱导的机制;和3）在正常人中由MSC建立细胞增殖的作用。骨免疫学和老年骨中的作用。定义兼性吞噬/吞噬作用在代谢中的作用 MSC中的变化和衰老及其与人类衰老和疾病的相关性将提供创新，影响针对骨骼的退行性疾病的可行策略。