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December 28, 2017

Obesity Leaves Lasting Impression on Blood-Forming Stem Cells

This micrograph shows bone marrow cellularity and composition in a genetically modified obese mouse (bottom). [Cincinnati Children's]

  • Obesity continues to weigh on the blood-forming stem cell compartment, altering the balance of the cell types produced there, even after the body sheds excess weight. Under the stress of obesity, hematopoietic stem cells (HSCs) begin to overexpress a regulatory gene that tilts blood production toward myeloid cells, and may even promote preleukemic fates. This shift in gene expression, which worsens over time, results in lasting dysregulation, even if HSCs are transplanted into a normal environment.

    Although these findings come from a study that relied on a mouse model of obesity, they raise questions about the use of HSCs isolated from obese people in therapeutic transplant procedures.

    "Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment," said Damien Reynaud, Ph.D., the study leader and an assistant professor at Cincinnati Children's Hospital Medical Center. "We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors."

    Study details appeared December 27 in the Journal of Experimental Medicine, in an article entitled  “Obesity Alters the Long-Term Fitness of the Hematopoietic Stem Cell Compartment through Modulation of Gfi1 Expression.” As the article’s title indicates, Dr. Reynaud’s research team traced the dysregulation of the HSC compartment to altered expression of Gfi1, a transcription factor.

    “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,” wrote the article’s authors. “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.”

    Obesity, the authors noted, is a chronic organismal stress that disrupts multiple systemic and tissue-specific functions. In the current study, the authors decided to investigate the impact of obesity on the activity of the HSC compartment.

    "There is now an understanding that the blood stem cell compartment is made up of numerous cell subsets," explained Dr. Reynaud. "Keeping this compartment healthy is essential to human health. This includes maintaining the diverse pool of blood-making stem cells needed to produce blood cells the body needs to function properly."

    Although the effects of chronic organismal stresses are still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in our blood-making machinery. Extending this research, the current study provides phenotypic and mechanistic insight into durable hematopoietic dysregulations resulting from obesity.

    Dr. Reynaud and colleagues added that their study also provides groundwork to investigate how lifestyle choices, such as diet, can durably impact blood formation and may contribute to the development of blood cancer.

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