Efferocytosis by Bone Marrow Stromal Cells and Bone Aging

骨髓基质细胞的胞吞作用和骨老化

• 批准号: 10629389
• 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
• 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/10629389
• 关键词: AMD3100; Acceleration; Address; Adult; Aging; Apoptosis; Apoptotic; BAI1 gene; Biology; Bone Marrow; Bone marrow failure; CXCL1 gene; CXCR4 gene; Cell Aging; Cell Senescence Induction; Cell physiology; 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; Macrophage; Maintenance; Malignant neoplasm of pancreas; Measures; Mediating; Mesenchymal; Metabolic; Metals; Mission; Mitochondria; Modeling; Molecular; Mus; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress Induction; Pathogenicity; Pathologic; Phagocytes; Phagocytosis; Phenotype; Physiology; Population; Process; Public Health; Reactive Oxygen Species; Reporting; Role; Signal Transduction; Skeleton; Stromal Cell-Derived Factor 1; Stromal Cells; Tamoxifen; Testing; Transgenic Organisms; United States National Institutes of Health; age related; aged; antagonist; antioxidant enzyme; biomechanical test; bone; bone aging; bone health; bone loss; bone repair; bone turnover; catalase; disability; drug repurposing; gain of function; improved; in vivo; inhibitor; innovation; loss of function; malignant breast neoplasm; mesenchymal stromal cell; mitochondrial dysfunction; mouse model; neutrophil; novel; novel therapeutics; osteoblast differentiation; osteogenic; osteoimmunology; overexpression; particle; pathogen; pharmacologic; preclinical study; prevent; programs; receptor; response; senescence; serine receptor; single-cell RNA sequencing; skeletal; stem

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 MSC增强骨细胞增多可能有益于骨骼健康。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。