Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression.
Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression.
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DOI：
10.1084/jem.20170690
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发表时间：
2018-02-05
期刊：
影响因子：
--
通讯作者：
Reynaud D
中科院分区：
文献类型：
--
作者：
Lee JM;Govindarajah V;Goddard B;Hinge A;Muench DE;Filippi MD;Aronow B;Cancelas JA;Salomonis N;Grimes HL;Reynaud D
Lee等人表明，已确定的肥胖改变了造血干细胞（HSC）区室的组成和长期适应性，部分原因是通过Gfi 1依赖性HSC调节程序，该程序由与这种状况相关的慢性氧化应激激活。肥胖是一种慢性的机体应激，它会破坏多种系统和组织特异性功能。在这项研究中，我们描述了肥胖对造血干细胞（HSC）室活性的影响。我们发现，肥胖改变了HSC的成分和它的活性，以应对造血压力。肥胖对HSC功能的影响是逐渐获得的，但在体重减轻或移植到正常环境后仍持续存在。从机制上讲，我们建立了由肥胖引起的氧化应激失调的转录因子Gfi1的表达，并增加Gfi1的表达所需的异常HSC功能由肥胖引起的。这些结果表明，肥胖症产生持久的变化，在HSC的功能和表型和Gfi1表达的升高，在氧化环境的反应是一个关键的驱动因素，在肥胖症中观察到的改变HSC的属性。总而言之，这些数据提供了持久的造血功能失调引起的肥胖症的表型和机制的见解。
Lee et al. show that established obesity alters the composition and long-term fitness of the hematopoietic stem cell (HSC) compartment, in part through a Gfi1-dependent HSC regulatory program that is activated by the chronic oxidative stress associated with this condition. Obesity is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. In this study, we describe the impact of obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity alters the composition of the HSC compartment and its activity in response to hematopoietic stress. The impact of obesity on HSC function is progressively acquired but persists after weight loss or transplantation into a normal environment. Mechanistically, we establish that the oxidative stress induced by obesity dysregulates the expression of the transcription factor Gfi1 and that increased Gfi1 expression is required for the abnormal HSC function induced by obesity. These results demonstrate that obesity produces durable changes in HSC function and phenotype and that elevation of Gfi1 expression in response to the oxidative environment is a key driver of the altered HSC properties observed in obesity. Altogether, these data provide phenotypic and mechanistic insight into durable hematopoietic dysregulations resulting from obesity.
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