Hematopoietic stem cell function in a murine model of sickle cell disease.
Hematopoietic stem cell function in a murine model of sickle cell disease.
复制标题
镰状细胞病小鼠模型中的造血干细胞功能。
作者：
Javazon,ElisabethH;Radhi,Mohamed;Gangadharan,Bagirath;Perry,Jennifer;Archer,DavidR
以往的研究表明，镰状环境高度富集活性氧（ROS）。我们在镰状细胞小鼠模型中检测了镰状细胞病对造血干细胞功能的氧化作用。体外菌落形成试验显示，与对照骨髓（BM）相比，镰状细胞衍生的祖菌落形成显著减少。镰状骨髓中KSL （c‐kit+、Sca‐1+、Lineage−）祖细胞数量显著减少，细胞周期分析显示，与对照组相比，处于细胞周期g0期的KSL细胞数量较少。我们发现镰状源性KSL细胞中脂质过氧化和ROS显著增加。体内分析表明，与对照小鼠相比，正常骨髓细胞植入镰状小鼠的频率更高。然而，来自镰状小鼠的造血祖细胞在移植潜能方面表现出明显的损伤。我们观察到移植前用n -乙酰半胱氨酸（NAC）处理KSL细胞可以部分恢复移植。NAC处理后细胞内ROS和脂质过氧化的增加以及移植的改善表明，镰状小鼠氧化还原环境的改变会影响造血祖细胞和干细胞的功能。
Previous studies have shown that the sickle environment is highly enriched for reactive oxygen species (ROS). We examined the oxidative effects of sickle cell disease on hematopoietic stem cell function in a sickle mouse model.In vitrocolony‐forming assays showed a significant decrease in progenitor colony formation derived from sickle compared to control bone marrow (BM). Sickle BM possessed a significant decrease in the KSL (c‐kit+, Sca‐1+, Lineage−) progenitor population, and cell cycle analysis showed that there were fewer KSL cells in the G0phase of the cell cycle compared to controls. We found a significant increase in both lipid peroxidation and ROS in sickle‐derived KSL cells.In vivoanalysis demonstrated that normal bone marrow cells engraft with increased frequency into sickle mice compared to control mice. Hematopoietic progenitor cells derived from sickle mice, however, demonstrated significant impairment in engraftment potential. We observed partial restoration of engraftment by n‐acetyl cysteine (NAC) treatment of KSL cells prior to transplantation. Increased intracellular ROS and lipid peroxidation combined with improvement in engraftment following NAC treatment suggests that an altered redox environment in sickle mice affects hematopoietic progenitor and stem cell function.