CCR5 Signaling Promotes Murine and Human Hematopoietic Regeneration following Ionizing Radiation

Abstract

Hematopoietic stem and progenitor cells (HSPCs) depend on regulatory cytokines from the marrow microenvironment. From an unbiased cytokine screen of murine marrow supernatants, we identified C-C motif chemokine ligand 5 (CCL5) as an endothelial cell-secreted hematopoietic growth factor. Following treatment with CCL5, hematopoietic regeneration is accelerated and survival is prolonged after radiation. In mice with deletion of Ccr5, hematopoietic regeneration is delayed compared to control mice. Deletion of Ccr5 specifically in hematopoietic cells was sufficient to delay regeneration, while the deletion of Ccr5 in stromal/endothelial cells was not. Mechanistically, CCL5 promotes hematopoietic cell cycling and cell survival. Like murine hematopoietic cells, human hematopoietic cells (cord blood, healthy marrow, and peripheral blood) increase CCR5 expression after radiation exposure to promote cell survival. These data establish that CCL5 and CCR5 signaling play critical roles in hematopoietic regeneration and could serve as therapeutic targets to shorten the duration of myelosuppression.

Keywords: CCL5; CCR5; RANTES; endothelial cell; hematopoietic cytokine; hematopoietic growth factor; hematopoietic microenvironment; hematopoietic stem cell; regeneration; vascular niche.