Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization

Abstract

Endocannabinoids are arachidonic acid derivatives and part of a novel bioactive lipid signaling system, along with their G-coupled cannabinoid receptors (CB 1 and CB 2 ) 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 CB 2 receptors are expressed in human and murine HSPCs. On ligand stimulation with CB 2 agonists, CB 2 receptors induced chemotaxis, migration, and enhanced colony formation of bone marrow cells, which were mediated via ERK, PI3-kinase, and G␣i-Rac1 pathways. In vivo, the CB 2 agonist AM1241 induced mobilization of murine HSPCs with shortand long-term repopulating abilities. In addition, granulocyte colony-stimulating factor -induced mobilization of HSPCs was significantly decreased by specific CB 2 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 CB 2 /CB 2 agonist axis mediates repopulation of hematopoiesis and mobilization of HSPCs. Thus, CB 2 agonists may be therapeutically applied in clinical conditions, such as bone marrow transplantation. (Blood. 2011;117(3):827-838) IntroductionEndocannabinoids and exogenous cannabinoid ligands bind to and activate the cannabinoid receptors CB 1 and CB 2 . 1-3 Endocannabinoids are endogenous lipid mediators generated by many cell types both in the brain and peripheral tissues, which exert a broad range of biologic effects, such as cardiovascular, neurologic, and antiinflammatory effects. 4 Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the 2 most widely studied endocannabinoids. The endocannabinoid system represents a pivotal neuroprotective mechanism both in acute forms of neuronal injury (such as stroke and traumatic brain injury) and chronic neurodegenerative disorders. [4][5][6][7][8] The synthetic and natural ligands of cannabinoid receptors exert various anti-inflammatory and neuroprotective effects by several mechanisms that include inhibiting the generation and release of proinflammatory cytokines, activation of cytoprotective signaling pathways, modulation of calcium homeostasis, and excitability via interactions with Ca ϩ2 , K ϩ , and Na ϩ channels as well as antioxidant properties of endocannabinoids. [4][5][6][7][8] Both the CB 1 and CB 2 receptors are 7-transmembrane G␣/i protein-coupled receptors (GPCRs) and are highly conserved during evolution. 2,9 The CB 2 receptor is predominantly expressed in the immune system, such as B and T cells, natural killer cells, monocytes, and neutrophils, where cannabinoids can modulate cytokine release and immune cell migration. Although the expression and function of cannabinoid receptors in mature hematologic and immune cells were reported, 9-14 the effect of cannabinoids on hematopoietic stem and pro...

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

“…In this context, it is noteworthy that eCBs can be counted among factors that govern haematopoietic stem cell biology. In bone marrow, CB receptors are highly expressed in haematopoietic stem cells, [51][52][53] and stromal cells release significant amounts of eCBs that modulate differentiation and migration, alone or in synergy with classical growth factors. 51,52 Therefore, it is tempting to speculate that pharmacological alteration of 2-AG tone in specialized niches of bone marrow would affect self-renewal and differentiation of haematopoietic cells, as well as lineage commitment.…”

Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart

“…Therefore, it is necessary to provide new strategies to activate CPCs with cardiac regenerative potential in situ by drug, cytokine, or growth factor intervention [2]. Interestingly, the CB2 receptor activation was shown to promote activation and proliferation of some types of endogenous stem cells (e.g., hematopoietic stem/progenitor cells and neural progenitor cells) in vivo [8,9]. However, it is still unknown whether the CB2 receptor sensitization can activate endogenous cardiac progenitor cells in situ, which needs to be further investigated.…”

“…Interestingly, Palazuelos et al [8] revealed that CB2-selective agonists promoted neural progenitor cell proliferation via activating the PI3K/Akt/mTORC1 signaling pathway. Moreover, Jiang et al [9] reported that cannabinoid receptor 2 and its agonists modulated hematopoietic stem and progenitor cell mobilization and function. However, whether CB2 receptor sensitization could activate CPCs in situ and promote myocardial regeneration is still unknown.…”

The haematopoietic stem cell niche at a glance

“…Integrity and regeneration of bone marrow vasculature are, indeed, fundamental for HSC recovery from myeloablative injuries and following bone marrow transplantation (Hooper et al, 2009;Kobayashi et al, 2010). Several reports agree on the location of functional, engrafting haematopoietic stem and progenitor cells (HSPCs, Box 1) being near the endosteal surface but not exclusively adjacent to osteoblastic cells (Jiang et al, 2009;Lo Celso et al, 2009;Xie et al, 2009). Whereas endosteal surfaces are highly vascularised, the question remains whether HSCs that are located at varying distances from osteoblastic cells are functionally distinct from those located near osteoblastic cells.…”

“…Integrins interact with ECM proteins, but integrin a4b1 is also the main binding partner of vascular cell adhesion molecule 1 (VCAM1), which is expressed on the surface of endothelial cells (Ulyanova et al, 2007) as well as cells of the osteoblastic lineage (Jiang et al, 2009). Interestingly, VCAM1 expression correlates with HSC homing (Lewandowski et al, 2010) and is upregulated in response to WNT signalling (Malhotra and Kincade, 2009a).…”