G-CSF deregulates niches and causes HSC mobilization. (A) G-CSF activates CD68⁺ CD169⁺ macrophages in perivascular niches. This suppresses macrophage supportive function for MSCs. Consequently, expression of CXCL12, SCF, and VCAM-1 is down-regulated. Complement cascade is activated, leading to erythrocyte lysis and release of S1P in the blood, creating a chemotactic counter gradient. Active HSCs are mobilized. (B) G-CSF suppresses osteomacs in endosteal niches. Osteoblasts are lost, bone formation stops, and expression of CXCL12, SCF, and VCAM-1 by MSCs and osteoprogenitors is down-regulated. Dormant HSCs are mobilized. (C) Schematic representation of interactions in response to G-CSF. β-adrenergic neuron activation by G-CSF inhibits SDF-1 production by MSCs, osteoprogenitors, and osteoblasts and inhibits bone formation by osteoblasts (solid red bars). Stimulation of osteomacs and CD169⁺ macrophages by G-CSF (solid red bars) suppresses their supportive function for MSCs and osteoblasts. Consequently, expression of SDF-1, Kit ligand, and VCAM-1 by osteoprogenitors and MSCs is down-regulated. Complement cascade is activated by G-CSF, resulting in S1P release into the blood.