Obesity-induced dysfunction of human MSC in peripheral microvascular repair

肥胖引起的人间充质干细胞在外周微血管修复中的功能障碍

• 批准号: 10653231
• 负责人: Alfonso Eirin
• 金额: $ 69.18万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653231
• 关键词: Address; Adipose tissue; Age; Attenuated; Biological Models; Blood Vessels; Bobcat; Body Weight decreased; Bone Marrow; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Clinical; Cost Savings; Cytosine; Diabetes Mellitus; Down-Regulation; Endocrine; Endothelial Cells; Enhancers; Enzyme Inhibitor Drugs; Epidemic; Epigenetic Process; Event; Exhibits; Family suidae; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Genes; Harvest; Histones; Human; Impairment; In Vitro; Inflammation; Injury; Ischemia; Kidney; Kidney Diseases; Life Style Modification; Link; Magnetic Resonance Imaging; Mediating; Mesenchymal; Metabolic; Methods; Methylation; MicroRNAs; Mitochondria; Mitochondrial DNA; Modification; Mus; Obesity; Organ; Pathogenesis; Patients; Peptide antibodies; Peptides; Peripheral; Peripheral Vascular Diseases; Peripheral arterial disease; Plasma; Predisposition; Prevalence; Process; Property; Quality of life; Regulation; Renal Artery Stenosis; Role; Sampling; Secondary to; Stromal Cells; Structure; System; Techniques; Testing; Therapeutic; Thinness; Tissues; Vascular Diseases; angiogenesis; bariatric surgery; cardiovascular risk factor; cell injury; citrate carrier; critical limb Ischemia; effective therapy; falls; functional disability; human subject; improved; in vivo; in vivo imaging; injured; injury recovery; microCT; mitochondrial dysfunction; mortality risk; mouse model; neutralizing antibody; novel; obese patients; paracrine; promoter; protective effect; protein expression; repair function; repaired; reparative capacity; restoration; stem; tissue repair; tool; transcriptome sequencing

Abstract Obesity triggers cellular damage and impedes tissue recovery from injury, and its escalating prevalence may promote complications of peripheral vascular disease, such as critical limb ischemia (CLI) or renal artery stenosis (RAS). Reducing complications of obesity could diminish the risk of death, improve quality of life, and produce extensive cost savings. This application is based on the scientific premise that obesity increases tissue susceptibility to injury by interfering with normal defense and repair processes associated with mesenchymal stem/stromal cells (MSCs). MSCs constitute an effective endogenous cellular repair system, but obesity may blunt their efficacy. We found that obesity-induced MSC dysfunction in pigs was associated with altered mitochondrial structure and function, but the mechanisms of mitochondrial damage in human MSC and its contribution to regulation of MSC function in human obesity remain unknown. Our central hypothesis is that human obesity engages epigenetic mechanisms that impair human MSC mitochondrial structure and function and render MSC functionally deficient. We speculate that obesity alters in MSC the epigenetic states of micro-RNA (miR) miR-181a, a key miR that targets mitochondrial DNA and negatively regulates their function. A consequent fall in levels of the mitochondrial derived peptide (MDP) MOTS-c in turn impairs function and tissue repair capacity of MSC in obesity. To test our hypothesis, we will define gene expression and epigenetic states of mitochondrial targeting miRNAs and MOTS-c in human adipose tissue-derived MSC and elucidate their functional significance for both MSCs and their mitochondria. Our Specific Aims will pursue 3 hypotheses. Aim 1: Human obesity induces MSC miR-181a expression and in turn mitochondrial and MSC structural damage and dysfunction. Using RNA-seq we will identify miR-181a as a key miR upregulated in MSCs from patients with obesity vs. healthy controls. Its role in regulating MSC and mitochondrial function and structure will be assessed in vitro and in vivo (in mice with CLI or RAS) using novel in vivo imaging and ex vivo techniques. Aim 2: Human obesity engages epigenetic mechanisms to alter miR- 181a. We will define the epigenetic landscape of miR-181a using MeDIP-seq, and its contribution to MSC repair in vitro and in vivo using an epigenetic modifier. Aim 3: A fall in MOTS-c owing to mitochondrial damage contributes to functional impairment of ‘obese MSC’. Using novel MDP-seq we will pinpoint MOTS-c as a unique MDP linking mitochondrial to cellular integrity in MSC. MSC treated with MOTS-c peptide or neutralizing antibody will be characterized, and restoration of ‘obese’ MSC function tested both in vitro and in vivo. The proposed studies, employing cutting edge techniques, may uncover novel mechanisms underlying cell damage and impaired repair in human obesity. These studies will advance understanding of the pathogenesis of cellular damage, and likely contribute towards management of patients with obesity and vascular disease.

抽象的 肥胖会引发细胞损伤并阻碍组织从损伤中恢复，其患病率不断上升 可能会促进周围血管疾病的并发症，例如严重肢体缺血（CLI）、肾或动脉 狭窄 (RAS) 减少肥胖并发症可以降低死亡风险，提高生活质量， 该应用基于肥胖增加这一科学前提。 通过干扰与相关的正常防御和修复过程，组织对损伤的敏感性 间充质干细胞/基质细胞（MSC）构成有效的内源性细胞修复系统， 但肥胖可能会削弱其功效，我们发现肥胖引起的猪间充质干细胞功能障碍与之相关。 线粒体结构和功能发生改变，但人类 MSC 中线粒体损伤的机制 其对人类肥胖中 MSC 功能调节的贡献仍不清楚。 我们的中心假设是人类肥胖涉及损害人类 MSC 的表观遗传机制 我们推测与肥胖有关的线粒体结构和功能并导致 MSC 功能缺陷。 改变 MSC 中微小 RNA (miR) miR-181a 的表观遗传状态，miR-181a 是靶向线粒体 DNA 的关键 miR 并对其功能产生负面调节，从而导致线粒体衍生肽 (MDP) 水平下降。 MOTS-c 反过来会损害肥胖中 MSC 的功能和组织修复能力。为了验证我们的假设，我们将进行验证。 定义人类线粒体靶向 miRNA 和 MOTS-c 的基因表达和表观遗传状态 脂肪组织来源的间充质干细胞，并阐明它们对间充质干细胞及其线粒体的功能意义。 我们的具体目标将追求 3 个假设 目标 1：人类肥胖诱导 MSC miR-181a 表达和 反过来，使用 RNA-seq，我们将线粒体和 MSC 结构损伤和功能障碍识别为 miR-181a。 与健康对照相比，肥胖患者的 MSC 中一个关键的 miR 上调，其在调节 MSC 和 MSC 中的作用。 线粒体功能和结构将使用新颖的方法在体外和体内（在患有 CLI 或 RAS 的小鼠中）进行评估 体内成像和离体技术 目标 2：人类肥胖利用表观遗传机制来改变 miR- 181a.我们将使用 MeDIP-seq 定义 miR-181a 的表观遗传景观及其对 MSC 的贡献 使用表观遗传修饰剂进行体外和体内修复 目标 3：由于线粒体损伤而导致 MOTS-c 下降。 使用新颖的 MDP-seq，我们将确定 MOTS-c 是一种导致“肥胖 MSC”功能损伤的因素。 在用 MOTS-c 肽或中和处理的 MSC 中，独特的 MDP 将线粒体与细胞完整性联系起来。 抗体将被表征，并在体外和体内测试“肥胖”MSC功能的恢复。 拟议的研究采用尖端技术，可能会揭示细胞的新机制 这些研究将促进对人类肥胖症发病机制的了解。 细胞损伤，并可能有助于肥胖和血管疾病患者的治疗。

项目成果

Metabolic Syndrome Induces Epigenetic Alterations in Mitochondria-Related Genes in Swine Mesenchymal Stem Cells.

代谢综合征诱导猪间充质干细胞线粒体相关基因的表观遗传改变。

• 发表时间: 2023-04-27
• 影响因子: 6
• 作者: Rajagopalan, Kamalnath S;Kazeminia, Sara;Glasstetter, Logan M;Farahani, Rahele A;Zhu, Xiang;Tang, Hui;Jordan, Kyra L;Chade, Alejandro R;Lerman, Amir;Lerman, Lilach O;Eirin, Alfonso
• 通讯作者: Eirin, Alfonso

Obesity Blunts the Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles.

肥胖会削弱间充质干细胞衍生的细胞外囊泡的作用。

• 发表时间: 2023-09
• 影响因子: 6
• 作者: Huang, Weijun;Hong, Siting;Zhu, Xiangyang;Alsaeedi, Mina H;Tang, Hui;Krier, James D;Gandhi, Deep;Jordan, Kyra L;Saadiq, Ishran M;Jiang, Yamei;Eirin, Alfonso;Lerman, Lilach O
• 通讯作者: Lerman, Lilach O