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.

项目概要 随着人们年龄的增长，生命早期接触环境污染物或毒素可能会改变健康状况。 早产儿就是一个典型的例子，因为他们的肺部过早地暴露于过量的空气中。 这些人在出生时就面临生长障碍、肺功能下降、宿主受损的风险。 我们确定了随着年龄的增长，人们对病毒性呼吸道感染的反应以及心血管疾病的发展。 一种独特的小鼠模型，在出生时暴露于高水平的氧气（高氧）会导致肺和心脏损伤 利用这个模型，我们现在提供了新的证据，表明新生儿高氧也会损害生长。 通过抑制从这些小鼠中分离出的骨髓间充质干细胞（BMSC）的生长。 它们的脂质积累和分化能力也降低。 脂肪细胞，可能是因为它们表达更高水平的 5'-AMP 激活蛋白激酶 (AMPK)，这是一种主要的 能量稳态调节剂，抑制脂肪酸合成和细胞增殖。 干细胞随着年龄的增长而增加，我们将检验新生儿高氧加速氧化的假设 随着小鼠年龄的增长，间充质干细胞的数量会增加，从而改变它们分化和产生脂肪的能力。 目标 1，我们将确定新生儿高氧如何永久重新编程氧化态，从而 骨、脂肪和肺 MSC 的分化，因为转基因 SftpcEC-SOD 小鼠没有观察到生长衰竭。 暴露于高氧环境中，目标 2 将确定抗​​氧化剂细胞外超氧化物是否过度表达 2 型肺泡上皮细胞的歧化酶可恢复 MSC 的氧化状态和成脂潜力。 还将确定 EC-SOD 是否保留支持 AT2 的相邻脂肪成纤维细胞的分化 细胞稳态的影响：了解新生儿高氧如何破坏脂肪生成。 重要的是，因为它将增加我们对早产如何改变以后生活健康的理解。