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:10312008
- 负责人:
- 金额:$ 64.16万
- 依托单位:
- 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 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipose tissueAgeAgingAttenuatedBiological ModelsBiopsyBody Weight decreasedCardiovascular DiseasesCell AgingCell Cycle ArrestCell physiologyCellsChronicChronic Kidney FailureClinicalControl GroupsCost SavingsDataDiabetes MellitusDiseaseDyslipidemiasEndocrineEpidemicExhibitsFamily suidaeFatty acid glycerol estersFibrosisFunctional disorderGenesHarvestHomeostasisHomingHumanHypertensionImaging TechniquesImmuneImpairmentIn VitroInflammationInflammatoryInjuryInjury to KidneyInsulin ResistanceKidneyLife Style ModificationLiver diseasesMalignant NeoplasmsMediatingMembraneMesenchymal Stem CellsMetabolicMicrovascular DysfunctionMorbidity - disease rateMusNutrientObesityOrganParentsPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhenotypePrevalenceProcessQuality of lifeRenal Artery StenosisRisk FactorsSecondary toStressSystemTechniquesTestingThinnessTissuesabdominal fatbariatric surgerycardiovascular risk factorcell injurychemokinecytokineeffective therapyextracellular vesiclesfisetinfunctional disabilityhuman subjectimprovedinjuredinjury and repairkidney repairmortalitymortality risknovelnovel strategiesobese patientsobese personparacrineprematureprogramsrepairedreparative capacityresponsesenescencestem cell functiontissue injurytranscriptome sequencingvesicular 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
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 影响因子:0
- 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:
- 影响因子:0
- 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:
- 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
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Lilach O Lerman其他文献
Endothelium-dependent coronary microvascular dysfunction is associated with advanced coronary plaque characteristics in patients with nonobstructive coronary atherosclerosis
内皮依赖性冠状动脉微血管功能障碍与非阻塞性冠状动脉粥样硬化患者的晚期冠状动脉斑块特征相关
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Shigeo Godo;Michel T Corban;Takumi Toya;Rajiv Gulati;Lilach O Lerman;Amir Lerman - 通讯作者:
Amir Lerman
Coronary microvascular endothelial dysfunction is associated with advanced coronary plaque characteristics in patients with early coronary atherosclerosis
冠状动脉微血管内皮功能障碍与早期冠状动脉粥样硬化患者的晚期冠状动脉斑块特征相关
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Shigeo Godo;Michel T Corban;Takumi Toya;Rajiv Gulati;Lilach O Lerman;Amir Lerman - 通讯作者:
Amir Lerman
Coronary microvascular endothelial dysfunction is an independent predictor of larger epicardial plaque area and higher plaque burden
冠状动脉微血管内皮功能障碍是较大心外膜斑块面积和较高斑块负荷的独立预测因素
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Michel T Corban;Shigeo Godo;Rajiv Gulati;Lilach O Lerman;Amir Lerman - 通讯作者:
Amir Lerman
Coronary microvascular endothelial dysfunction is associated with plaque vulnerability in patients with early coronary atherosclerosis
早期冠状动脉粥样硬化患者冠状动脉微血管内皮功能障碍与斑块易损性相关
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Shigeo Godo;Michel T Corban;Rajiv Gulati;Lilach O Lerman;Amir Lerman - 通讯作者:
Amir Lerman
1027-189 Chronic endothelin receptor antagonism preserves endothelial function in a transgenic mouse model of alzheimer's disease
- DOI:
10.1016/s0735-1097(04)91902-x - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Ahmad A Elesber;Piero Bonetti;Joerg Herrmann;Julie Woodrum;Steven Younkin;Lilach O Lerman;Amir Lerman - 通讯作者:
Amir Lerman
Lilach O Lerman的其他文献
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{{ truncateString('Lilach O Lerman', 18)}}的其他基金
Quantitative magnetization transfer MRI for evaluation of renal fibrosis
定量磁化转移 MRI 评估肾纤维化
- 批准号:
10337329 - 财政年份:2020
- 资助金额:
$ 64.16万 - 项目类别:
Noninvasive Evaluation of Renal Allograft Fibrosis by MRI
MRI 无创评估同种异体移植肾纤维化
- 批准号:
9976272 - 财政年份:2020
- 资助金额:
$ 64.16万 - 项目类别:
Quantitative magnetization transfer MRI for evaluation of renal fibrosis
定量磁化转移 MRI 评估肾纤维化
- 批准号:
10549318 - 财政年份:2020
- 资助金额:
$ 64.16万 - 项目类别:
Noninvasive Evaluation of Renal Allograft Fibrosis by MRI
MRI 无创评估同种异体移植肾纤维化
- 批准号:
10176331 - 财政年份:2020
- 资助金额:
$ 64.16万 - 项目类别:
Obesity-induced mesenchymal stem cell senescence
肥胖引起的间充质干细胞衰老
- 批准号:
10062968 - 财政年份:2018
- 资助金额:
$ 64.16万 - 项目类别:
MSC-derived microvesicles in metabolic syndrome and renovascular disease
间充质干细胞衍生的微泡在代谢综合征和肾血管疾病中的作用
- 批准号:
9231450 - 财政年份:2015
- 资助金额:
$ 64.16万 - 项目类别:
Hypoxia and inflammatory injury in human renovascular hypertension
人类肾血管性高血压的缺氧和炎症损伤
- 批准号:
8722682 - 财政年份:2014
- 资助金额:
$ 64.16万 - 项目类别:
Noninvasive assessment of renal fibrosis using magnetization transfer MRI
使用磁化转移 MRI 无创评估肾纤维化
- 批准号:
9352889 - 财政年份:2014
- 资助金额:
$ 64.16万 - 项目类别:
Low-Energy Shockwave Treatment Distal To Peripheral Vascular Disease
低能量冲击波治疗远端周围血管疾病
- 批准号:
8617434 - 财政年份:2014
- 资助金额:
$ 64.16万 - 项目类别:
Hypoxia and inflammatory injury in human renovascular hypertension
人类肾血管性高血压的缺氧和炎症损伤
- 批准号:
9049492 - 财政年份:2014
- 资助金额:
$ 64.16万 - 项目类别:
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