Decisive role of P42/44 mitogen-activated protein kinase in Δ9-tetrahydrocannabinol-induced migration of human mesenchymal stem cells

Abstract

In past years, medical interest in Δ⁹-tetrahydrocannabinol (THC), the major psychoactive ingredient of the Cannabis plant, has been renewed due to the elucidation of the endocannabinoid system and diverse other receptor targets involved in biological cannabinoid effects. The present study therefore investigates the impact of THC on the migration of mesenchymal stem cells (MSCs) which are known to be involved in various regenerative processes such as bone healing. Using Boyden chamber assays, THC was found to increase the migration of adipose-derived MSCs. Migration by THC was almost completely suppressed by the CB₁ receptor antagonist AM-251 and to a lesser extent by the CB₂ receptor antagonist AM-630. By contrast, the TRPV1 antagonist capsazepine as well as the G protein-coupled receptor 55 (GRP55) agonist O-1602 did not significantly interfere with the promigratory effect of THC. Furthermore, increased migration by THC was fully suppressed by PD98059, an inhibitor of p42/44 mitogen-activated protein kinase (MAPK) activation, and was accompanied by a time-dependent activation of this pathway accordingly. In line with the migration data, additional inhibitor experiments pointed towards a decisive role of the CB₁ receptor in conferring THC-induced activation of p42/44 MAPK. Collectively, this study demonstrates THC to exert a promigratory effect on MSCs via a CB₁ receptor-dependent activation of p42/44 MAPK phosphorylation. This pathway may be involved in regenerative effects of THC and could be a target of pharmacological intervention.