Obesity-induced mesenchymal stem cell senescence

肥胖引起的间充质干细胞衰老

基本信息

批准号：
10062968
负责人：
Lilach O Lerman
金额：
$ 64.16万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-27 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062968
关键词：
Address Adipose tissue Age Aging Attenuated Biological Models Biopsy Body Weight decreased Cardiovascular Diseases Cell Aging Cell Cycle Arrest Cell physiology Cells Chronic Chronic Kidney Failure Clinical Control Groups Cost Savings Data Diabetes Mellitus Disease Dyslipidemias Endocrine Epidemic Exhibits Family suidae Fatty acid glycerol esters Fibrosis Functional disorder Genes Harvest Homeostasis Homing Human Hypertension Imaging Techniques Immune Impairment In Vitro Inflammation Inflammatory Injury Injury to Kidney Insulin Resistance Kidney Life Style Modification Liver diseases Malignant Neoplasms Mediating Membrane Mesenchymal Stem Cells Metabolic Microvascular Dysfunction Morbidity - disease rate Mus Nutrient Obesity Organ Parents Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Prevalence Process Quality of life Renal Artery Stenosis Risk Factors Secondary to Stress System Techniques Testing Thinness Tissues abdominal fat bariatric surgery cardiovascular risk factor cell injury chemokine cytokine effective therapy extracellular vesicles fisetin functional disability human subject improved injured injury and repair kidney repair mortality mortality risk novel novel strategies obese patients obese person paracrine premature programs repaired reparative capacity response senescence stem cell function tissue injury transcriptome sequencing vesicular release

项目摘要

ABSTRACT/SUMMARY The prevalence of obesity is rising to epidemic proportions. Obesity often leads to endocrine and metabolic derangements, and reduction in its complications could diminish morbidity and mortality, and produce large cost savings. Currently, bariatric surgery is considered the most effective treatment for sustainable weight loss. Obesity triggers cellular damage in multiple organs, partly via induction of premature senescence. This cellular program is characterized by a permanent cell-cycle arrest and altered cellular function, which prompts cells to acquire a senescence-associated secretory phenotype (SASP), a distinctive secretome that involves secretion of inflammatory cytokines and chemokines. Aberrant accumulation of senescent cells exhibiting the SASP phenotype exerts noxious effects on neighboring cells, and drives tissue injury and the aging phenotype. Mesenchymal stem cells (MSC), a ubiquitous cellular repair mechanism, may be injured by ambient risk factors. In obesity adipose tissue-derived MSC might develop cellular senescence (CS) and acquire a SASP phenotype, suggesting that obesity may impede endogenous cellular repair capacity. However, the effects of obesity on CS in human MSC, and the impact of MSC CS on their reparative capacity, remain unknown. Our hypothesis is that obesity evokes senescence in human MSC, which interferes with their capacity to repair injured kidneys. We hypothesize that this impaired MSC function is partly mediated by a phenotype shift in MSC-derived extracellular vesicles (EV) that drive their paracrine effects, but would be reversible upon senolytic pre-treatment of MSC, or following patient weight loss. We will use unique and novel model systems and techniques to pursue specific aims showing that: Specific Aim 1: In human subjects, obesity induces CS in adipose tissue MSC, and interferes with their repair capacity in injured mouse kidneys. Specific Aim 2: The functional impairment in adipose tissue MSC from obese human subjects is partly mediated by a phenotype shift in their membrane-derived EV. Specific Aim 3: MSC-CS and SASP in obese human subjects would be reversible upon bariatric surgery. The proposed studies may uncover novel mechanisms, involving impaired circulating and tissue cellular repair systems, which underlie complications of human obesity. Furthermore, they may establish a novel strategy to blunt this injurious cellular senescence, and thereby boost endogenous kidney repair capability.

摘要/总结肥胖症的患病率正在上升到流行病的程度。肥胖往往会导致内分泌和代谢紊乱紊乱及其并发症的减少可以降低发病率和死亡率，并产生大量节省成本。目前，减肥手术被认为是可持续减肥的最有效治疗方法。肥胖会引发多个器官的细胞损伤，部分原因是诱导过早衰老。这细胞程序的特点是永久性细胞周期停滞和细胞功能改变，这提示细胞获得衰老相关的分泌表型（SASP），这是一种独特的分泌组，涉及炎症细胞因子和趋化因子的分泌。衰老细胞的异常积累表现出 SASP 表型对邻近细胞产生有害影响，并导致组织损伤和衰老表型。间充质干细胞（MSC）是一种普遍存在的细胞修复机制，可能会因环境风险而受损因素。在肥胖症中，脂肪组织来源的 MSC 可能会发生细胞衰老 (CS) 并获得 SASP 表型，表明肥胖可能阻碍内源性细胞修复能力。然而，影响肥胖对人类 MSC 的 CS 以及 MSC CS 对其修复能力的影响仍不清楚。我们的假设是肥胖会引起人类 MSC 的衰老，从而干扰其能力修复受伤的肾脏。我们假设这种受损的 MSC 功能部分是由 MSC 衍生的细胞外囊泡 (EV) 的表型转变驱动其旁分泌作用，但会在 MSC 的 senolytic 预处理后或患者体重减轻后可逆转。我们将用独特且追求特定目标的新颖模型系统和技术表明：特定目标 1：在人类中研究人员发现，肥胖会诱导脂肪组织 MSC 发生 CS，并干扰受损小鼠的修复能力肾脏。具体目标 2：来自肥胖人类受试者的脂肪组织 MSC 的功能损伤是部分是由膜源性 EV 的表型转变介导的。具体目标 3：MSC-CS 和 SASP 肥胖的人类受试者通过减肥手术将得到逆转。拟议的研究可能会揭示新的机制，涉及循环和组织细胞受损修复系统，这是人类肥胖并发症的基础。此外，他们可能会建立一个小说减缓这种有害细胞衰老的策略，从而增强内源性肾脏修复能力。