Obesity-induced mesenchymal stem cell senescence

肥胖引起的间充质干细胞衰老

• 批准号: 10312008
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-27 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312008
• 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

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 肥胖症的流行正在上升到流行病的程度。肥胖往往导致内分泌和代谢 紊乱，减少其并发症可以降低发病率和死亡率，并产生大量的 节约成本。目前，减肥手术被认为是可持续减肥的最有效治疗方法。 肥胖引发多个器官的细胞损伤，部分是通过诱导过早衰老。这 细胞程序的特征是永久性的细胞周期停滞和细胞功能的改变， 细胞获得衰老相关的分泌表型（SASP），一个独特的分泌组，涉及 炎性细胞因子和趋化因子的分泌。衰老细胞的异常积累， SASP表型对邻近细胞产生有害作用，并驱动组织损伤和衰老表型。 间充质干细胞（MSC），一种普遍存在的细胞修复机制，可能会受到环境风险的损伤 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，表明肥胖可能会阻碍内源性细胞修复能力。然而， 肥胖对人MSC中CS的影响以及MSC CS对其修复能力的影响仍然未知。 我们的假设是，肥胖引起人MSC的衰老，这干扰了它们的能力。 修复受损的肾脏我们假设这种受损的MSC功能部分是由一种 MSC衍生的细胞外囊泡（EV）中的表型转变驱动其旁分泌效应，但 在MSC的衰老清除预处理后或在患者体重减轻后是可逆的。我们将使用独特的和 追求特定目标的新模型系统和技术表明：特定目标1：在人类 受试者中，肥胖诱导脂肪组织MSC中的CS，并干扰其在损伤小鼠中的修复能力 肾脏具体目的2：研究来自肥胖人类受试者的脂肪组织MSC中的功能损伤。 部分由其膜衍生EV的表型转变介导。具体目标3：MSC-CS和SASP 肥胖的人类受试者在减肥手术后是可逆的。 拟议的研究可能揭示新的机制，涉及受损的循环和组织细胞， 修复系统，这是人类肥胖并发症的基础。此外，他们可以建立一个小说， 这是一种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。

项目成果

Efficacy of Human Embryonic Stem Cells Compared to Adipose Tissue-Derived Human Mesenchymal Stem/Stromal Cells for Repair of Murine Post-Stenotic Kidneys.

与脂肪组织来源的人间充质干细胞/基质细胞相比，人胚胎干细胞修复小鼠狭窄后肾脏的功效。

• DOI: 10.1007/s12015-022-10443-8
• 发表时间: 2023
• 期刊: Stem cell reviews and reports
• 影响因子: 4.8
• 作者: Siddiqi,Sarosh;Klomjit,Nattawat;Jiang,Kai;Conley,SabenaM;Zhu,Xianyang;Saadiq,IshranM;Ferguson,ChristopherM;Tang,Hui;Lerman,Amir;Lerman,LilachO
• 通讯作者: Lerman,LilachO

Prognostic impact and clinical outcomes of coronary flow reserve and hyperaemic microvascular resistance.

冠状动脉血流储备和充血性微血管阻力的预后影响和临床结果。

• DOI: 10.4244/eij-d-20-00853
• 发表时间: 2021
• 期刊: EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology
• 作者: Toya,Takumi;Corban,MichelT;Park,JiYoung;Ahmad,Ali;Ӧzcan,Ilke;Sebaali,Faten;Sara,JaskanwalDS;Gulati,Rajiv;Lerman,LilachO;Lerman,Amir
• 通讯作者: Lerman,Amir

Correlation of Intravascular Ultrasound and Instantaneous Wave-Free Ratio in Patients With Intermediate Left Main Coronary Artery Disease.

• DOI: 10.1161/circinterventions.120.009830
• 发表时间: 2021-06
• 期刊: Circulation. Cardiovascular interventions
• 作者: El Hajj SC;Toya T;Warisawa T;Nan J;Lewis BR;Cook CM;Rajkumar C;Howard JP;Seligman H;Ahmad Y;Doi S;Nakajima A;Nakayama M;Goto S;Vera-Urquiza R;Sato T;Kikuta Y;Kawase Y;Nishina H;Nakamura S;Matsuo H;Escaned J;Akashi YJ;Davies JE;Lerman A
• 通讯作者: Lerman A

Comparable in vitro Function of Human Liver-Derived and Adipose Tissue-Derived Mesenchymal Stromal Cells: Implications for Cell-Based Therapy.

• DOI: 10.3389/fcell.2021.641792
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Yigitbilek F;Conley SM;Tang H;Saadiq IM;Jordan KL;Lerman LO;Taner T
• 通讯作者: Taner T