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

项目摘要 在生命早期暴露于环境污染物或毒素会随着年龄的增长而改变健康和健身。 早产儿就是一个很好的例子，因为他们的肺暴露得太快，而且经常暴露在过量的 出生时的氧气这些个体随后处于生长失败、肺功能降低、宿主受损的风险中。 对呼吸道病毒感染的反应，以及随着年龄的增长而发生心血管疾病。我们建立 一种独特的小鼠模型，其中出生时暴露于高水平的氧气（高氧）导致肺和心脏 病后的生活使用这个模型，我们现在提供了新的证据，新生儿高氧也损害生长 通过抑制脂肪积累。从这些小鼠中分离的骨髓间充质干细胞（BMSCs）生长 速度更慢，氧化程度更高。他们还显示出降低的能力，积累脂质和分化成 脂肪细胞，可能是因为它们表达了更高水平的5'-AMP活化蛋白激酶（AMPK），这是一种主要的 抑制脂肪酸合成和细胞增殖的能量平衡调节器。由于氧化 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， 随着小鼠年龄的增长，间充质干细胞的数量增加，从而改变了它们分化和产生脂肪的能力。在 目的1，我们将确定新生儿高氧如何永久性地重新编程氧化状态， 骨、脂肪和肺MSC的分化。由于当转基因SftpcEC-SOD小鼠 暴露于高氧，目标2将确定是否过度表达抗氧化剂细胞外超氧化物 通过肺泡上皮2型细胞的歧化酶恢复MSC的氧化状态和成脂潜力。我们 还将确定EC-SOD是否保留了支持AT 2的相邻脂肪成纤维细胞的分化 细胞内稳态对该领域的影响：了解新生儿高氧如何破坏脂肪形成， 重要的是，它将增加我们对早产如何改变生命后期健康的理解。

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.