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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

基本信息

批准号：
10516515
负责人：
Alfonso Eirin
金额：
$ 70.66万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/10516515
关键词：
Address Adipose tissue Age Attenuated Biological Models 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 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 base 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

项目摘要

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.