Regulation of hematopoietic stem cell trafficking and mobilization by the endocannabinoid system

Abstract

The cannabinoid receptors CB(1) and CB(2) are seven-transmembrane Gαi protein-coupled receptors and are expressed in certain mature hematopoietic cells. We recently showed that these receptors are expressed in murine and human hematopoietic stem cells (HSCs) and that CB(2) agonists induced chemotaxis, enhanced colony formation of marrow cells, as well as caused in vivo mobilization of murine HSCs with short- and long-term repopulating abilities. Based on these observations, we have further explored the role of CB(2) and its agonist AM1241 on hematopoietic recovery following sublethal irradiation in mice. Cannabinoid receptor 2 knockout mice (Cnr2(-/-) deficient mice) exhibited impaired recovery following sublethal irradiation as compared with irradiated wild-type (WT) mice, as determined by low colony-forming units and low peripheral blood counts. WT mice treated with CB(2) agonist AM1241 following sublethal irradiation demonstrated accelerated marrow recovery and increased total marrow cells (approximately twofold) and total lineage- c-kit(+) cells (approximately sevenfold) as well as enhanced HSC survival as compared with vehicle control-treated mice. When the CB(2) agonist AM1241 was administered to WT mice 12 days before their sublethal irradiation, analysis of hematopoiesis in these mice showed decreased apoptosis of HSCs, enhanced survival of HSCs, as well as increase in total marrow cells and c-kit+ cells in the marrow. Thus, CB(2) agonist AM1241 promoted recovery after sublethal irradiation by inhibiting apoptosis of HSCs and promoting survival, as well as enhancing the number of HSCs entering the cell cycle.

Endocannabinoids Control Platelet Activation and Limit Aggregate Formation under Flow

“…Interestingly, this mechanism could also reflect an innate ‘preservation’ pathway present in platelets, meant to prevent premature activation of platelets in the bone marrow niche. Indeed, there is evidence that the endocannabinoid system is active in the bone marrow: the cannabinoid receptor Cb2 is expressed by hematopoietic cell lines and endocannabinoids reportedly regulate cells in the bone marrow environment [12], [13]. Based on our findings, it is attractive to think that endocannabinoids instruct platelets to be less sensitive to triggers that are likely to be present in uninjured bone marrow (i.e.…”

“…Anandamide (N-arachidonylethanolamine) is one of the best-characterized endocannabinoids. It interacts both with CB 1 and CB 2 receptors and is present in the bone marrow microenvironment, where it regulates hematopoietic cells [12], [13]. Anandamide is a short-lived molecule, which is rapidly degraded by fatty acid amide hydrolase (FAAH).…”

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.…”

“…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. 54 In addition, owing to the specific effect of 2-AG on megakaryocyte precursors, it would be helpful to manage bone marrow failure and blood cell loss occurring in several pathological conditions.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Endocannabinoids induce migration and trafficking of hematopoietic stem and progenitor cells from the bone marrow to the peripheral blood. Therefore, the ECS is a physiological regulator of hematopoiesis (401). It seems, however, that the two main endocannabinoids may play different roles in this context: AEA reduces, while 2-AG enhances, bone marrow cell migration, and both enhance the formation of granulocyte, erythrocyte, macrophage, and megakaryocyte colonies, AEA being more potent than 2-AG (666).…”