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Updated: May 3, 2026
Assessment of Cellular Bioenergetics in Mouse Hematopoietic Stem and Primitive Progenitor Cells using the Extracellular Flux Analyzer
Published on: September 24, 2021
Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells
Guodong Tie1, Katharine E Messina, Jinglian Yan
1Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, Worcester, MA.
Insights
High cholesterol accelerates hematopoietic stem cell aging by inducing oxidative stress. This impairs their function and repopulation capacity, but can be reversed with antioxidants.
Area of Science:
- Hematology
- Stem Cell Biology
- Cardiovascular Research
Background:
- Clinical studies link hypercholesterolemia to hematopoietic stem cell (HSC) aging.
- Ageing-associated alterations observed in blood cells and bone marrow precursors of atherosclerosis patients.
- Hypothesis: Hypercholesterolemia induces oxidative stress, accelerating HSC aging.
Purpose of the Study:
- To investigate the impact of hypercholesterolemia on HSC aging.
- To determine if oxidative stress mediates hypercholesterolemia-induced HSC aging.
- To explore potential therapeutic interventions.
Main Methods:
- Utilized ApoE(-/-) and high cholesterol diet (HCD) C57Bl/6 mouse models.
- Analyzed HSCs for oxLDL accumulation, ROS levels, gene expression, and cell cycle regulators.
- Assessed HSC function including telomere length and repopulation capacity.
- Investigated the role of p38 MAPK and Notch1 signaling pathways.
- Evaluated the effect of N-acetylcysteine (antioxidant) treatment.
Main Results:
- HSCs from hypercholesterolemic mice showed increased oxLDL and ROS levels.
- Significant reduction in long-term HSCs, telomere length, and repopulation capacity observed.
- Upregulation of cell cycle inhibitors (p19ARF, p27Kip1, p21Waf1) and aberrant Notch1 expression.
- p38-dependent pathway identified; effects reversed by N-acetylcysteine.
- Oxidative stress led to loss of HSC quiescence and proliferation.
Conclusions:
- Hypercholesterolemia induces oxidative stress in HSCs.
- This oxidative stress accelerates HSC aging and impairs their reconstitution capacity.
- Targeting oxidative stress may be a therapeutic strategy for HSC dysfunction in hypercholesterolemia.
Background:
Clinical studies suggest that hypercholesterolemia may cause ageing in hematopoietic stem cells (HSCs) because ageing-associated alterations were found in peripheral blood cells and their bone marrow residing precursors in patients with advanced atherosclerosis. We hypothesized that hypercholesterolemia induces oxidant stress in hematopoietic stems cells that accelerates their ageing.
Methods And Results:
Here we show that HSCs from ApoE(-/-) mice, as well as HSCs from C57Bl/6 mice fed a high cholesterol diet (HCD) accumulated oxLDL and had greater ROS levels. In accordance, the expression pattern of the genes involved in ROS metabolism changed significantly in HSCs from ApoE(-/-) mice. Hypercholesterolemia caused a significant reduction in phenotypically defined long-term HSC compartment, telomere length, and repopulation capacity of KTLS cells, indicating accelerated ageing in these cells. Gene array analysis suggested abnormal cell cycle status, and the key cell cycle regulators including p19(ARF), p27(Kip1) and p21(Waf1) were upregulated in KTLS cells from hypercholesterolemic mice. These effects were p38-dependent and reversed in vivo by treatment of hypercholesterolemic mice with antioxidant N-acetylcysteine. The oxidant stress also caused aberrant expression of Notch1 that caused loss of quiescence and proliferation leading to the expansion of KTLS compartment in hypercholesterolemic mice.
Conclusion:
Taken together, we provide evidence that hypercholesterolemia can cause oxidant stress that accelerates the ageing and impairs the reconstitution capacity of HSCs.
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