Epigenetic programming of infant mesenchymal stem cells: mechanisms for obesity and diabetes risk in humans

婴儿间充质干细胞的表观遗传编程：人类肥胖和糖尿病风险的机制

• 批准号: 10441451
• 负责人: Kristen Elizabeth Boyle
• 金额: $ 29.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441451
• 关键词: 5' -AMP-activated protein kinase; Address; Animal Model; Animals; Basic Science; Biological Assay; Birth; Body mass index; Cellular Metabolic Process; Child; Citric Acid Cycle; Clinical; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Electron Transport; Energy Metabolism; Enzymes; Epigenetic Process; Exhibits; Fasting; Fatty Acids; Fatty acid glycerol esters; Genes; Genetic; Glucose; Goals; Health; Human; Hyperinsulinism; Hypermethylation; Impairment; In Vitro; Infant; Insulin; Insulin Resistance; Investigation; Knowledge; Lead; Life; Lipids; Maternal Exposure; Measures; Mesenchymal Stem Cells; Metabolic; Metabolic stress; Metabolism; Methylation; Mitochondria; Modeling; Molecular; Mothers; Nutrient; Obesity; Outcome; Overweight; Pathway interactions; Phenotype; Physical activity; Play; Population Sciences; Prevention; Prevention strategy; Protein Kinase; Publishing; Regulation; Reporter; Resources; Risk; Role; Sampling; Skeletal Muscle; Stimulus; Succinate Dehydrogenase; System; Testing; Tissues; Umbilical Cord Blood; Umbilical cord structure; Weight; Woman; clinically relevant; cohort; diabetes risk; fatty acid oxidation; fetal; in utero; infant adiposity; infant outcome; knock-down; lifestyle factors; lipid metabolism; maternal obesity; metabolic phenotype; mitochondrial dysfunction; myogenesis; neonatal outcome; novel; novel therapeutic intervention; nutrition; obese mothers; obesity in pregnancy; obesity prevention; obesity risk; offspring; offspring obesity; overexpression; oxidation; prepregnancy; response; stem cell model; translational approach

PROJECT SUMMARY/ABSTRACT Children born to mothers with obesity are at increased risk for developing obesity and diabetes later in life, independent of lifestyle factors, such as physical activity or nutrition. While some children born to obese mothers will not go on to develop obesity or insulin resistance, for those who do, little is known about how maternal exposures (e.g., hyperinsulinemia) may influence child outcomes in humans. We use human, infant mesenchymal stem cells (MSCs), cultured from umbilical cord tissue collected at birth, for investigating mechanisms of obesity and diabetes risk in humans. Human and animal studies, as well as our own MSC data, show strong association between maternal, MSC and infant metabolism. For example, MSCs from infants born to obese vs. normal weight mothers have perturbations in lipid metabolism and energy sensing molecules regulating lipid metabolism, such as AMP-activated protein kinase (AMPK), which we observed at the epigenetic level (DNA methylation). Ob-MSCs also have impaired AMPK activation in response to metabolic stress in vitro, which could compromise lipid partitioning and shifts in fuel utilization in response to metabolic stimuli. Moreover, MSC lipid metabolism correlates with fat mass of the infants measured at birth. These observations make this a novel model in which to investigate the epigenetic programming of human metabolic phenotypes in vitro. Our unique, translational approach allows us to maintain human variability in a basic science model. Such integration of mechanistic investigation with clinical samples will help us to achieve our long-term goal of understanding mechanisms for the developmental programming of metabolism at the molecular level in humans. This project will not only advance the field for understanding the molecular underpinnings of human developmental programming, but may also identify modifiable maternal factors contributing to offspring phenotype supporting implementation of critically needed obesity prevention strategies. Therefore, the central hypothesis for this proposal is that perturbations in maternal metabolism induce infant MSC epigenetic signatures promoting dysregulation of cellular fuel switching and mitochondrial dysfunction. This project leverages our unique resource of MSCs already collected from >150 infants as part of a well characterized, longitudinal pre-birth cohort (Healthy Start, R01DK076648). Thus, while Aims 1&2 will determine mechanisms for altered lipid partitioning and mitochondrial dysfunction in MSCs from infants born to normal weight versus obese mothers, Aim 3 will expand this knowledge to population science, validating our preliminary data in a larger cohort. Aim 1 will determine the impact of maternal obesity-induced epigenetic signatures on offspring MSC fuel switching and lipid partitioning in response to changes in nutrient supply. Aim 2 will determine whether epigenetic signature promotes mitochondrial dysfunction and reduced substrate oxidation in Ob- vs. NW-MSCs. Aim 3 will substantiate the clinical relevance of the umbilical cord MSC model using specific tests to determine maternal metabolic measures predictive of MSC metabolism and, in turn, MSC metabolic measures predictive of infant outcomes.

项目摘要/摘要 患有肥胖症的母亲所生的孩子在以后的生活中患肥胖症和糖尿病的风险增加， 独立于生活方式因素，如身体活动或营养。一些肥胖母亲所生的孩子 不会继续发展肥胖或胰岛素抵抗，对于那些这样做的人，很少有人知道母亲如何 暴露（例如，高胰岛素血症）可能会影响人类的儿童结局。我们用人类，婴儿 间充质干细胞（MSC），培养从脐带组织收集在出生时，用于研究 肥胖和糖尿病风险的机制。人类和动物研究，以及我们自己的MSC数据， 显示母体、MSC和婴儿代谢之间强关联。例如，来自出生于 与正常体重的母亲相比，肥胖母亲的脂质代谢和能量感应分子受到干扰 调节脂质代谢，如AMP激活的蛋白激酶（AMPK），我们在表观遗传学上观察到， DNA甲基化（DNA methylation）Ob-MSC在体外也具有响应于代谢应激的受损的AMPK活化， 这可能损害脂质分配和响应于代谢刺激的燃料利用的变化。此外，委员会认为， MSC脂质代谢与出生时测量的婴儿脂肪量相关。这些观察使这一点成为 新的模型，在其中研究人类代谢表型的表观遗传编程在体外。我们 独特的转化方法使我们能够在基本的科学模型中保持人类的变异性。这种结合 对临床样本的机制研究将有助于我们实现我们的长期目标， 在人类分子水平上代谢的发育编程机制。这个项目 不仅将推进对人类发育的分子基础的理解， 编程，但也可以确定可修改的母体因素有助于后代表型支持 实施急需的肥胖预防战略。因此，这个问题的核心假设 建议母体代谢的扰动诱导婴儿MSC表观遗传标记促进 细胞燃料转换失调和线粒体功能障碍。这个项目利用了我们独特的资源 已经从>150名婴儿收集的MSC作为良好表征的纵向出生前队列的一部分（健康 开始，R 01 DK 076648）。因此，虽然目标1和2将确定改变脂质分配的机制， 出生体重正常的婴儿与肥胖母亲的骨髓间充质干细胞线粒体功能障碍，目标3将扩大 这一知识的人口科学，验证我们的初步数据在一个更大的队列。目标1将决定 母体肥胖诱导表观遗传标记对后代MSC燃料转换和脂质分配的影响 以应对营养供应的变化。目标2将确定表观遗传特征是否促进 Ob-与NW-MSC相比，线粒体功能障碍和底物氧化减少。目标3将证实 使用特定试验确定母体代谢的脐带MSC模型的临床相关性 测量MSC代谢的预测性，并且反过来，MSC代谢测量预测婴儿结果。

项目成果

Precision stratification of prognostic risk factors associated with outcomes in gestational diabetes mellitus: a systematic review.

• DOI: 10.1038/s43856-023-00427-1
• 发表时间: 2024-01-12
• 期刊: COMMUNICATIONS MEDICINE
• 作者: Semnani-Azad, Zhila;Gaillard, Romy;Hughes, Alice E;Boyle, Kristen E;Tobias, Deirdre K;Perng, Wei
• 通讯作者: Perng, Wei

Programmed epigenetic risk: Can stress exposures in utero predispose infants to obesity and metabolic diseases?

程序化表观遗传风险：子宫内的压力暴露会使婴儿容易患上肥胖和代谢疾病吗？

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Boyle,KristenE