title: 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.
abstract: 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.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Northeastern University, Boston, Massachusetts 02215, USA.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Jiang
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Zagozdzon
authors.forename: Meritxell Alberich
authors.initials: MA
authors.lastname: Jorda
authors.forename: Kalindi
authors.initials: K
authors.lastname: Parmar
authors.forename: Yigong
authors.initials: Y
authors.lastname: Fu
authors.forename: John S
authors.initials: JS
authors.lastname: Williams
authors.forename: Jodi Anne T
authors.initials: JA
authors.lastname: Wood
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.forename: Naheed
authors.initials: N
authors.lastname: Banu
authors.forename: Shalom
authors.initials: S
authors.lastname: Avraham
authors.forename: Jerome E
authors.initials: JE
authors.lastname: Groopman
authors.forename: Hava Karsenty
authors.initials: HK
authors.lastname: Avraham
mesh_terms: 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
chemical_list: 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
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