Obesity Alters the Composition and the Activity of the Hematopoietic Stem Cell Compartment Through Dysregulation of Gfi1 Expression (single-cell 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. Overall design: Single cell RNA seq to identify the gene expression changes associated with obesity in murine CD150+CD48-LSK HSCs. HSCs were isolated from WT and leptin-receptor mutant mice (db/db) at 4 and 14 months of age.