Role of early life hyperoxia on mesenchymal stem cell fate: their impact on age related disease

生命早期高氧对间充质干细胞命运的作用：它们对年龄相关疾病的影响

• 批准号: 10312537
• 负责人: Michael A O'Reilly
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312537
• 关键词: 5' -AMP-activated protein kinase; Adipocytes; Adult; Affect; Age; Air; Antioxidants; Awareness; Birth; Bone Marrow; Cardiac Myocytes; Cardiovascular Diseases; Cartoons; Cell Proliferation; Cell physiology; Cells; Chondrocytes; Cyclic AMP-Dependent Protein Kinases; Development; Diastolic heart failure; Disease; Environmental Pollutants; Exposure to; Failure; Fatty Acids; Fatty acid glycerol esters; Genetic Transcription; Goals; Grant; Growth; Harvest; Health; Heart Atrium; Heart Diseases; Homeostasis; Human; Hyperoxia; Immune response; Impairment; Individual; Influenza A virus; Left; Left atrial structure; Life; Lipids; Longevity; Lung; Lung diseases; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modeling; Mus; Myofibroblast; Neonatal Hyperoxic Injury; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen; Pharmacology; Phenotype; Premature Birth; Premature Infant; Production; Public Health; Pulmonary veins; Research; Risk; Risk Factors; Role; Source; Superoxide Dismutase; Testing; Therapeutic; Time; Tissue Differentiation; Toxic Environmental Substances; Transgenic Organisms; Viral Respiratory Tract Infection; age related; alveolar epithelium; bone; bone marrow mesenchymal stem cell; donor stem cell; extracellular; fitness; genetic approach; improved; influenza virus strain; insight; lipid biosynthesis; mouse model; neonatal infection; novel therapeutics; overexpression; oxidation; postnatal; preservation; prevent; pulmonary function; repaired; stem cell fate; stem cells; stemness

PROJECT SUMMARY Exposure to environmental pollutants or toxins early in life can alter health and fitness as people age. Preterm infants are a prime example because their lungs are exposed too soon and often to excess amounts of oxygen at birth. These individuals are then at risk for growth failure, reduced lung function, impaired host response to respiratory viral infections, and development of cardiovascular disease as they age. We established a unique mouse model wherein exposure to high levels of oxygen (hyperoxia) at birth causes lung and heart disease later in life. Using this model, we now provide new evidence that neonatal hyperoxia also impairs growth by inhibiting fat accumulation. Bone marrow mesenchymal stem cells (BMSCs) isolated from these mice grew slower and were more oxidized. They also displayed reduced capacity to accumulate lipid and differentiate into adipocytes, possibly because they expressed higher levels of 5’-AMP activated protein kinase (AMPK), a master regulator of energy homeostasis that inhibits fatty acid synthesis and cell proliferation. Since the oxidation of stem cells increases with age, we will test the hypothesis that neonatal hyperoxia accelerates the oxidation of mesenchymal stem cells as mice age, thereby altering their ability to differentiate and produce fat. In Aim 1, we will determine how neonatal hyperoxia permanently reprograms the oxidation state and thus differentiation of bone, fat, and lung MSCs. Since growth failure is not seen when transgenic SftpcEC-SOD mice are exposed to hyperoxia, Aim 2 will determine if over-expression of the anti-oxidant extracellular superoxide dismutase by alveolar epithelial type 2 cells restores the oxidation state and adipogenic potential of MSCs. We will also determine whether EC-SOD preserves the differentiation of adjacent lipofibroblasts that support AT2 cell homeostasis. Impact on the Field: Understanding how neonatal hyperoxia disrupts adipogenesis is important because it will increase our understanding of how preterm birth alters health later in life.

项目摘要 随着人们的年龄增长，生命早期接触环境污染物或毒素会改变健康和健身。 早产儿是一个很好的例子，因为他们的肺暴露得太早，并且经常量过多 出生时的氧气。然后，这些人有生长失败的风险，肺功能降低，宿主受损 对呼吸道病毒感染的反应以及随着年龄的增长的心血管疾病的发展。我们建立了 一个独特的小鼠模型，其中暴露于高水平的氧气（高氧）出生会导致肺和心脏 疾病以后的生活。使用此模型，我们现在提供了新的证据，表明新生儿高氧还会损害生长 通过抑制脂肪的积累。从这些小鼠中分离的骨髓间充质干细胞（BMSCS）生长 较慢，被氧化更多。他们还显示出降低的脂肪的能力并分化为 脂肪细胞，可能是因为它们表达了较高水平的5'AMP激活蛋白激酶（AMPK），Master 由于能量稳态的氧化抑制了脂肪酸的合成和细胞增殖。 干细胞随着年龄的增长而增加，我们将测试新生儿高氧加速氧化的假设。 间充质干细胞的年龄，从而改变了它们分化和产生脂肪的能力。 AIM 1，我们将确定新生儿高氧如何永久重编程氧化态，从而如何 骨，脂肪和肺MSC的分化。由于转基因SFTPCEC-SOD小鼠未见生长失败 暴露于高氧，AIM 2将确定抗氧化细胞外超氧化物的过表达是否表达 肺泡上皮2型细胞的歧化酶恢复了MSC的氧化态和成脂潜力。我们 还将确定EC-SOD是否保留了支持AT2的相邻脂肪纤维细胞的分化 细胞体内稳态。对现场的影响：了解新生儿高氧如何破坏脂肪形成是 重要的是，因为它将增加我们对早产如何改变以后生活的理解。