Many studies have documented the mechanisms of homing of HSCs into the BM and recirculation of these BM HSCs into the blood. CXCR4+ HSCs are attracted to the BM by the SDF-1 chemokine produced by BM stromal cells. Binding of SDF1 to CXCR4 activates the very-late activation antigen type 4 (VLA-4) PS-341 chemical structure integrin of HSCs which can adhere to endothelial VCAM1+ cells.6 HSCs are recruited to SDF-1+ stromal cells which are adjacent to endothelial cells. Upon injury, HSCs migrate to the closest osteoblasts which produce various growth factors, such as granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6).7 More recently,

BM stromal cells have been shown to express β3 adrenergic receptors.8 Norepinephrine production learn more by the sympathetic nervous system controls expression of homing molecules by stromal cells. It is noteworthy that a circadian fluctuation of norepinephrine production results in circadian release of a minor population of HSCs into the PB. In mice, these circulating HSCs have been shown to play an important role in innate immune surveillance.9 Accordingly, circulating HSCs home to tissues where they may reside for 36 hr before returning to the PB through the lymphatic system. In the case of infection,

Toll-like receptor-mediated activation of HSCs results in down-regulation of the sphingosine phosphate receptor and in situ differentiation of HSCs into innate immune cells: tissue-resident Adenosine triphosphate myeloid cells, preferentially dendritic cells.10 This tightly controlled homing of HSCs into the BM and recirculation into the

PB may explain why human CD34+ HSCs injected into the PB can rapidly home to and engraft the BM and vice versa. At the same time, it may also explain why HSCs can be mobilized into the PB after CXCR4 antagonist or G-CSF injection.11 The effect of G-CSF is mainly attributable to activation of BM myeloid cells to produce proteases that cleave SDF-1 and adhesion molecules.8 Given the similarity of the PC and HSC BM niches in mice, it is tempting to postulate that similar mechanisms exist for the homing of PCs into the BM and eventually for their recirculation from the BM to the PB. Regarding PC homing, it has been shown that deletion of CXCR4 abrogates homing of murine PCs into the murine BM, similarly to HSCs.12 Regarding the exit of BM PCs into the PB, 2 CD19+ CD20− CD38++ PCs/mm3 have been reported in human adults in steady-state conditions.13,14 The origin of circulating PCs remains undetermined but they may be either newly generated PCs in the lymph node or long-lived tissue PCs. After vaccination with tetanus toxin (TT), there is a 4–5-fold increase in the number of circulating PCs, a significant fraction of which do not secrete anti-TT Abs.15 This suggests that newly generated PCs can displace old PCs from their niche and induce them to recirculate.