Endocannabinoids are expressed in bone marrow stromal niches and play a role in interactions of hematopoietic stem and progenitor cells with the bone marrow microenvironment.
Endocannabinoids are lipid signaling molecules that act via G-coupled receptors, CB(1) and CB(2). The endocannabinoid system is capable of activation of distinct signaling pathways on demand in response to pathogenic events or stimuli, hereby enhancing cell survival and promoting tissue repair. However, the role of endocannabinoids in hematopoietic stem and progenitor cells (HSPCs) and their interaction with hematopoietic stem cells (HSC) niches is not known. HSPCs are maintained in the quiescent state in bone marrow (BM) niches by intrinsic and extrinsic signaling. We report that HSPCs express the CB(1) receptors and that BM stromal cells secrete endocannabinoids, anandamide (AEA) (35 pg/10(7) cells), and 2-AG (75.2 ng/10(7) cells). In response to the endotoxin lipopolysaccharide (LPS), elevated levels of AEA (75.6 pg/10(7) cells) and 2-AG (98.8 ng/10(7) cells) were secreted from BM stromal cells, resulting in migration and trafficking of HSPCs from the BM niches to the peripheral blood. Furthermore, administration of exogenous cannabinoid CB(1) agonists in vivo induced chemotaxis, migration, and mobilization of human and murine HSPCs. Cannabinoid receptor knock-out mice Cnr1(-/-) showed a decrease in side population (SP) cells, whereas fatty acid amide hydrolase (FAAH)(-/-) mice, which have elevated levels of AEA, yielded increased colony formation as compared with WT mice. In addition, G-CSF-induced mobilization in vivo was modulated by endocannabinoids and was inhibited by specific cannabinoid antagonists as well as impaired in cannabinoid receptor knock-out mice Cnr1(-/-), as compared with WT mice. Thus, we propose a novel function of the endocannabinoid system, as a regulator of HSPC interactions with their BM niches, where endocannabinoids are expressed in HSC niches and under stress conditions, endocannabinoid expression levels are enhanced to induce HSPC migration for proper hematopoiesis.
Jiang
Shuxian
S
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Northeastern University, Boston, Massachusetts 02215, USA.
Zagozdzon
Radoslaw
R
Jorda
Meritxell Alberich
MA
Parmar
Kalindi
K
Fu
Yigong
Y
Williams
John S
JS
Wood
Jodi Anne T
JA
Makriyannis
Alexandros
A
Banu
Naheed
N
Avraham
Shalom
S
Groopman
Jerome E
JE
Avraham
Hava Karsenty
HK
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis* / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003511:Cyclohexanols / Q000494:pharmacology; D063388:Endocannabinoids; D005260:Female; D005434:Flow Cytometry; D005989:Glycerides / Q000096:biosynthesis; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000166:cytology / Q000378:metabolism; D055153:Stem Cell Niche / Q000166:cytology / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; C078814:anandamide
Curr Med Chem. 2010;17(14):1430-49
20166923
Bone Marrow Transplant. 2009 Nov;44(10):635-42
19802017
Curr Opin Hematol. 2010 Jul;17(4):308-12
20473159
Curr Opin Investig Drugs. 2010 Jan;11(1):51-62
20047159
Eur J Pharmacol. 2000 May 19;396(2-3):141-9
10822068
Curr Med Chem. 2010;17(14):1341-59
20166928
J Radiat Res. 1984 Mar;25(1):91-8
6737356
Stem Cell Res Ther. 2010 Jun 15;1(2):17
20550687
Curr Stem Cell Res Ther. 2008 Jan;3(1):9-16
18220918
Nat Rev Immunol. 2008 Apr;8(4):290-301
18323850
Curr Med Chem. 2010;17(14):1468-86
20166921
J Cell Physiol. 2010 Jan;222(1):17-22
19725055
Anal Chem. 2007 Aug 1;79(15):5582-93
17600384
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5780-5
10318961
Drug Discov Today. 2010 Jun;15(11-12):474-83
20304091
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9371-6
11470906
Biol Blood Marrow Transplant. 2010 Feb;16(2):147-56
20142045
Mol Pharmacol. 2006 Mar;69(3):1066-73
16368894
J Anat. 2009 Nov;215(5):477-97
19702867
J Exp Med. 1996 Apr 1;183(4):1797-806
8666936
BMC Med. 2009 Jun 11;7:29
19519878
Stem Cells Dev. 2010 Aug;19(8):1131-41
20148648
Nature. 1993 Sep 2;365(6441):61-5
7689702
J Exp Med. 2005 Apr 18;201(8):1307-18
15837815
Mol Immunol. 2006 Jul;43(14):2169-79
16503355
PLoS One. 2010 May 05;5(5):e10496
20463965
Int Immunopharmacol. 2010 May;10(5):547-55
20219697
J Neuroimmunol. 2004 Feb;147(1-2):91-4
14741435
Methods Mol Biol. 2008;430:55-75
18370291
Eur J Pharmacol. 2008 Oct 24;595(1-3):1-6
18778813
Life Sci. 1999;65(6-7):637-44
10462064
Curr Opin Genet Dev. 2009 Oct;19(5):461-8
19811902
Nature. 2009 May 7;459(7243):103-7
19322176
Biochem Pharmacol. 2010 Jul 1;80(1):1-12
20206137
Blood. 2009 May 28;113(22):5444-55
19324903
Curr Med Chem. 2010;17(14):1393-410
20166925
Cell Death Differ. 2007 Nov;14(11):1851-9
17823616
Transfus Apher Sci. 2008 Jun;38(3):261-8
18486554
J Leukoc Biol. 2005 Dec;78(6):1192-7
16204639
J Neuroendocrinol. 2008 May;20 Suppl 1:69-74
18426503
Nature. 1990 Aug 9;346(6284):561-4
2165569
J Intern Med. 2009 Oct;266(4):311-24
19765177
Cell Stem Cell. 2009 Jan 9;4(1):27-36
19128790