Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis.

Area of Science:

• Hematology
• Cardiovascular Science
• Genetics

Background:

• Clonal hematopoiesis, expansion of mutated hematopoietic stem cell clones, is linked to cardiovascular disease (CVD).
• Mechanisms connecting clonal hematopoiesis and CVD remain unclear.

Purpose of the Study:

• To investigate the role of hematopoietic stem cell (HSC) proliferation in the association between CVD and clonal hematopoiesis.
• To determine if increased HSC division rates contribute to clonal expansion in atherosclerosis.

Main Methods:

• Measured HSC division rates in mice and humans with atherosclerosis.
• Developed a mathematical model to assess the impact of proliferation on clonal evolution.
• Validated findings using mouse models of atherosclerosis and sleep fragmentation with Tet2-deficient HSC transplantation.

Main Results:

• HSC division rates are elevated in atherosclerosis patients and mice.
• Mathematical modeling shows increased proliferation accelerates somatic evolution and clonal expansion.
• Elevated division rates in patients predict a 3.5-fold increased risk of clonal hematopoiesis by age 70.
• Accelerated expansion of Tet2-/- HSCs observed under conditions of elevated hematopoietic activity.

Conclusions:

• Increased HSC proliferation is a key mechanism linking atherosclerosis and clonal hematopoiesis.
• Elevated stem cell division rates contribute significantly to the risk of developing clonal hematopoiesis in the context of CVD.