Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization.
Endocannabinoids are arachidonic acid derivatives and part of a novel bioactive lipid signaling system, along with their G-coupled cannabinoid receptors (CB₁ and CB₂) and the enzymes involved in their biosynthesis and degradation. However, their roles in hematopoiesis and hematopoietic stem and progenitor cell (HSPC) functions are not well characterized. Here, we show that bone marrow stromal cells express endocannabinoids (anandamide and 2-arachidonylglycerol), whereas CB₂ receptors are expressed in human and murine HSPCs. On ligand stimulation with CB₂ agonists, CB₂ receptors induced chemotaxis, migration, and enhanced colony formation of bone marrow cells, which were mediated via ERK, PI3-kinase, and Gαi-Rac1 pathways. In vivo, the CB₂ agonist AM1241 induced mobilization of murine HSPCs with short- and long-term repopulating abilities. In addition, granulocyte colony-stimulating factor -induced mobilization of HSPCs was significantly decreased by specific CB₂ antagonists and was impaired in Cnr2(-/-) cannabinoid type 2 receptor knockout mice. Taken together, these results demonstrate that the endocannabinoid system is involved in hematopoiesis and that CB₂/CB₂ agonist axis mediates repopulation of hematopoiesis and mobilization of HSPCs. Thus, CB₂ agonists may be therapeutically applied in clinical conditions, such as bone marrow transplantation.
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Shuxian
S
Jiang
Meritxell
M
Alberich-Jorda
Radoslaw
R
Zagozdzon
Kalindi
K
Parmar
Yigong
Y
Fu
Peter
P
Mauch
Naheed
N
Banu
Alexandros
A
Makriyannis
Daniel G
DG
Tenen
Shalom
S
Avraham
Jerome E
JE
Groopman
Hava Karsenty
HK
Avraham
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism
C439263:AM 1241; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D003511:Cyclohexanols; D008070:Lipopolysaccharides; D043885:Receptor, Cannabinoid, CB2; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC