Obesity Alters the Composition and the Activity of the Hematopoietic Stem Cell Compartment Through Dysregulation of Gfi1 Expression (Bulk RNA-Seq)

Obesity is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. Here, we describe the effects of established obesity on the activity of the hematopoietic stem cell (HSC) compartment. We show that obesity promotes the selection of a quiescent HSC subset primed for activation, leading to aberrant hematopoietic stress responses. We establish that the transcription factor Gfi1 is a key regulator of the HSC fate in obesity as its increased expression in obesity induces their abnormal activity. We demonstrate that these dysregulations are initially triggered by the chronic oxidative stress associated with obesity. Once acquired, we show that the impact of obesity on HSCs is long lasting and cannot be reversed by weight loss or transplantation. These results demonstrated that obesity promotes irreversible changes on the long-term fitness of the HSC compartment, a phenomenon that is likely to contribute to the hematopoietic dysregulations observed in obese patients.

肥胖是一种慢性机体应激状态，可破坏多系统及组织特异性的生理功能。本研究系统分析了成熟肥胖状态对造血干细胞（hematopoietic stem cell, HSC）池活性的影响。研究发现，肥胖可促使处于静息状态、已预激活的造血干细胞亚群被筛选富集，进而引发异常的造血应激应答。本研究证实，转录因子Gfi1是肥胖状态下造血干细胞命运调控的关键调节因子：肥胖时Gfi1表达上调，可诱导造血干细胞出现异常活性。研究表明，上述造血调控异常最初由肥胖伴随的慢性氧化应激触发。一旦该异常确立，肥胖对造血干细胞的影响将持续存在，且无法通过减重或造血干细胞移植逆转。本研究结果显示，肥胖可导致造血干细胞池的长期功能健康状态出现不可逆改变，这一现象或可促成肥胖患者中观察到的造血调控异常。