In this issue of Blood, Gomes and colleagues demonstrate that hypercholesterolemia in mice for 30 days induces dramatic alterations in hematopoiesis through CXCL12 (SDF-1)–mediated enhanced interaction of the hematopoietic cells with specialized bone marrow sinusoidal endothelial cells.1 This results in thrombocytosis, lymphocytosis, and increased mobilization of the progenitor cells to the peripheral circulation, possibly contributing to atherosclerosis.
Hypercholesterolemia has been associated with acceleration of atherosclerosis, resulting in ischemic heart and peripheral vascular diseases. It is believed that hypercholesterolemia through induction of inflammation promotes atheromas.2,3 However, the precise mechanism by which high cholesterol and LDL levels would foster atheroma formation remains known. In this report, it is demonstrated that hypercholesterolemia stimulates the release of CXCL12 (also known as stromal derived factor-1, SDF-1), which by stimulation of its receptor CXCR4 (CD184) increases the interaction of the megakaryocytes with the bone marrow sinusoidal endothelial cells, leading to increased thrombopoiesis. Elevation of CXCL12 within the bone marrow and circulation also augments the mobilization of CXCR4+ B lymphocytes and proangiogenic CXCR4-responsive hematopoietic progenitor cells (HPCs), known as hemangiocytes,4 to the peripheral circulation leading to significant lymphocytosis, while partially depleting myeloid precursors within the bone marrow. These data provide an explanation for the previously unrecognized etiology of thrombocytosis, lymphocytosis, and alteration in monocyte levels observed in hypercholesterolemic patients.2,3
High cholesterol primarily affects blood vessels within myocardium and large vessels. This is the first report linking hypercholesterolemia to functional alterations of a specialized vascular bed, such as sinusoidal endothelium within the bone marrow. The bone marrow vascular niche, demarcated by VEGFR3+ sinusoidal endothelial cells, has recently been shown to be essential for the maintenance and reconstitution of hematopoiesis,5 including thrombopoiesis.6-8 This report indicates that sinusoidal endothelial cells are not immune to hypercholesterolemia and their activation through alteration of hematopoietic equilibrium, such as induction of thrombocytosis and mobilization of the inflammatory cells, could contribute to systemic complications associated with hypercholesterolemia.
These results establish a novel concept as to how hypercholesterolemia through CXCL12-mediated recruitment of inflammatory and thrombotic cells might contribute to the development of atherosclerosis or even predispose patients to inflammatory-dependent malignancies. Hence, this report sets forth the provocative notion that therapeutic targeting of CXCR4 signaling might diminish certain end-organ complications associated with chronic hypercholesterolemia. Whether cholesterol-lowering agents commonly used to treat hypercholesterolemia also modulate the expression of CXCL12 or CXCR4 and decrease inflammation-dependent atheroma is not known.
These interesting findings notwithstanding, there are many unanswered questions. For example, the mechanism by which high cholesterol or LDH levels provoke CXCL12 release by the endothelial cells or other stromal cells needs to be determined. It is conceivable that HDL might prevent CXCL12-driven activation of hematopoiesis, thereby attenuating atheroma formation. The consequences of CXCL12-mediated lymphocytosis in the setting of hypercholesterolemia and progression of atherosclerosis requires further investigation. Nonetheless, this study has unraveled a drugable chemokine pathway that if targeted properly could benefit patients who suffer from complications associated with hypercholesterolemia.
Conflict-of-interest disclosure: The authors declare no competing financial interests. ■
National Institutes of Health