Cannabinoid Receptors CB1 and CB2 Regulate Mobilization of Hematopoietic Stem and Progenitor Cells

Endocannabinoids are lipid mediators that modulate central and peripheral neural functions as well as immune responses and bind to specific G-protein-coupled receptors:CB1 and CB2. Here, we investigated the role of CB1/CB2 and cognate cannabinoid ligands in hematopoietic stem and progenitor cell (HSPC) mobilization. CB1 and CB2receptor expression was observed in human and murine HSPCs. Cannabinoid ligands induced the chemotaxis of the human CD34+ cells and caused mobilization of murine HSPC in vivo. Inhibition of degradation of the endocannabinoid anandamide by URB597induced mobilization of HSPC and significantly augmented mobilization of these cells when URB597 was administered with G-CSF-, AMD3100- and with the combination of G-CSF+AMD3100. Moreover, the cannabinoid- or G-CSF-induced mobilization of HSPC was significantly impaired by cannabinoid receptor inhibitors and in CB1- andCB2-knockout mice. Administration of exogenous cannabinoid agonists in mice induced mobilization of progenitors as well as stem cells in vivo with long-term repopulating ability. These results demonstrate a novel pathway by which the cannabinoid system regulates HSPC cell trafficking, and may be therapeutically applied in clinical conditions, such as bone marrow transplantation.