Cooperation of beta(2)- and beta(3)-adrenergic receptors in hematopoietic progenitor cell mobilization

CXCL12/SDF-1 dynamically regulates hematopoietic stem cell (HSC) attraction in the bone marrow (BM). Circadian regulation of bone formation and HSC traffic is relayed in bone and BM by beta-adrenergic receptors (beta-AR) expressed on HSCs, osteoblasts, and mesenchymal stem/progenitor cells. Circadian HSC release from the BM follows rhythmic secretion of norepinephrine from nerve terminals, beta(3)-AR activation, and Cxcl12 downregulation, possibly from reduced Sp1 nuclear content. Here, we show that beta-AR stimulation in stromal cells causes Sp1 degradation, partially mediated by the 26S proteasome. Inverted trends of circulating hematopoietic progenitors and BM Cxcl12 mRNA levels change acutely after light onset, shown to induce sympathetic efferent activity. In BM stromal cells, activation of beta(3)-AR downregulates Cxcl12, whereas beta(2)-AR stimulation induces clock gene expression. Double deficiency in beta(2)- and beta(3)-ARs compromises enforced mobilization. Therefore, beta(2)- and beta(3)-ARs have specific roles in stromal cells and cooperate during progenitor mobilization.