ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation

Area of Science:

• Cardiovascular Biology
• Hematopoiesis
• Atherosclerosis Research

Background:

• Leukocytosis, particularly monocytosis, is linked to atherosclerosis.
• The mechanisms driving elevated leukocyte counts remain unclear.
• Adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1 are crucial for cholesterol efflux from macrophages and suppressing atherosclerosis.

Purpose of the Study:

• To investigate the role of ABCA1 and ABCG1 in regulating hematopoietic stem and progenitor cell populations.
• To understand the connection between ABC transporters, leukocytosis, and atherosclerosis development.

Main Methods:

• Generation and analysis of mice deficient in ABCA1 and ABCG1.
• Bone marrow transplantation experiments.
• Assessment of hematopoietic stem and progenitor cell populations (LSK).
• Evaluation of leukocytosis, myeloproliferative disorders, and atherosclerosis.

Main Results:

• Mice lacking ABCA1 and ABCG1 exhibited leukocytosis, a myeloproliferative disorder, and expansion of Lin(-)Sca-1(+)Kit+ (LSK) stem and progenitor cells.
• Transplantation of Abca1(-/-)Abcg1(-/-) bone marrow into high-density lipoprotein (HDL) transgenic mice suppressed LSK expansion and leukocytosis.
• This transplantation also reversed the myeloproliferative disorder but accelerated atherosclerosis.

Conclusions:

• ABCA1, ABCG1, and HDL play a critical inhibitory role in the proliferation of hematopoietic stem and multipotential progenitor cells.
• Expansion of these stem and progenitor cell populations is directly linked to leukocytosis and accelerated atherosclerosis.
• These findings establish a novel connection between cholesterol efflux pathways and the regulation of blood cell production in the context of atherosclerosis.