The Cannabinoid Receptor Type 2 as Mediator of Mesenchymal Stromal Cell Immunosuppressive Properties

Abstract

Mesenchymal stromal cells are non-hematopoietic, multipotent progenitor cells producing cytokines, chemokines, and extracellular matrix proteins that support hematopoietic stem cell survival and engraftment, influence immune effector cell development, maturation, and function, and inhibit alloreactive T-cell responses. The immunosuppressive properties of human mesenchymal stromal cells have attracted much attention from immunologists, stem cell biologists and clinicians.Recently, the presence of the endocannabinoid system in hematopoietic and neural stem cells has been demonstrated. Endocannabinoids, mainly acting through the cannabinoid receptor subtype 2, are able to modulate cytokine release and to act as immunosuppressant when added to activated T lymphocytes.In the present study, we have investigated, through a multidisciplinary approach, the involvement of the endocannabinoids in migration, viability and cytokine release of human mesenchymal stromal cells.We show, for the first time, that cultures of human mesenchymal stromal cells express all of the components of the endocannabinoid system, suggesting a potential role for the cannabinoid CB2 receptor as a mediator of anti-inflammatory properties of human mesenchymal stromal cells, as well as of their survival pathways and their capability to home and migrate towards endocannabinoid sources.

The immunomodulatory function of mesenchymal stem cells: mode of action and pathways

“…Furthermore, the possible involvement of the cannabinoid system in MSC function was recently reported . In this study, the authors described the inversely correlated expression of the receptors for the cannabinoids CB1 and CB2 on cultured MSCs, with levels of the CB2 receptor increasing with the maturation of the cells, and showed that MSCs also contain detectable amounts of cannabinoids .…”

The effect of hydroalcoholic extract of Cannabis Sativa on morphology and growth of bone marrow mesenchymal stem cells in rat

“…This effect is likely to be due to the antioxidant effect, anti-inflammatory properties, or the beneficial effects of cannabis extract along with growth factors, and this effect is also confirmed by the MTT result. The function of cannabinoid receptors, CB (1) and CB (2), can also be considered as components of a new regulatory pathway for the involvement of a cannabinoid system in the stem cell viability (2,4,8,9,15,16,19).…”

Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis

“…Upon CB2R activation, T cells undergo apoptosis and decreased proliferation in colitis. Additionally, activation of CB2R diminishes the recruitment of neutrophils, T cells and macrophages to the inflamed colon (Storr et al 2009;Singh et al 2012); reduces expression of adhesion molecules in brain endothelium, decreasing leukocyte engagement and recruitment (Ramirez et al 2012); attenuates monocytes adhesion to and migration across of primary human brain microvascular endothelial cells (Rom et al 2013); inhibits Th17 differentiation in experimental autoimmune encephalomyelitis (Kong et al 2014) and liver disease (Kong et al 2014;Guillot et al 2014); inhibits the production of proinflammatory cytokines (IL-1␤, IL-6, IL-8, TNF␣ and IL-17) in splenocytes (Gui et al 2013), in human mesenchymal stromal cells (Rossi et al 2013), and in iris and ciliary body tissue (Toguri et al 2014). Furthermore, activation of CB2R reduces neovascularization in a model of sponge-induced inflammatory angiogenesis (Guabiraba et al 2013), which might be helpful to suppress synovial angiogenesis and pannus formation in RA.…”