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.

Recruitment of Mesenchymal Stem Cells to Damaged Sites by Plant-Derived Components

“…Analgesic effects Kaur et al, 2016, Anti-inflamatory Schicho et al, 2011, Anti-gliomas Vaccani et al, 2005, Wound healing Wang et al, 2016, Bone formation Idris andRalston, 2012 Migration Schmuhl et al, 2014;Lüder et al, 2017, Osteocyte differentiation Schmuhl et al, 2014 Bone-defect Kamali et al, 2019 Icariin (ICA) Epimedium (Berberidaceae) Li et al, 2015 Anti-oxidant, Tonic, Aphrodisiac, Neuro-protective, Cardio-protective, Anti-rheumatic, Anti-cancer, Anti-osteoporotic Li et al, 2015, Wound healing by effects for keratinocyte proliferation and migration Mi et al, 2018, Improvement of periodontal pathology by effects for survival and migration of periodontal ligament fibroblasts Liu H. J. et al, 2018Migration Jiao et al, 2018Zhu et al, 2018, Proliferation, Osteocyte differentiation Qin et al, 2015, Chondrogenic differentiation Wang et al, 2014, Cell survival Wang X. et al, 2017, Neuronal regeneration in cooperation with MSCs Liu D. et al, 2018 Cartilage-defect Jiao et al, 2018, Diabetes-associated erectile dysfunction Wang X. et al, 2017, Cerebral ischemia Liu D. et al, 2018 Tanshinone IIA (Tan IIA) Salvia miltiorrhiza (Lamiaceae) Ren et al, 2019 Anti-oxidant, Anti-inflammatory, Cardio-protective, Neuro-protective, Vascular-protective, Anti-cancer Li et al, 2018a;Ren et al, 2019 Inhibition of vascular endothelial cell proliferation and migration in angiogenesis-related pathologies Xing et al, 2015;Fan et al, 2017;Lee et al, 2017Migration Tong et al, 2011, Osteogenic differentiation Qian e...…”

“…Similarly, the major psychoactive component, 9tetrahydrocannabinol ( 9-THC), also increased AMSC migration (Lüder et al, 2017). In the case of THC, migration of AMSCs is facilitated by CB1 through Erk1/2 activation, although THC has been reported to respond to both CB1 and CB2 (Pertwee, 2008).…”

Cannabinoid-Induced Autophagy and Heme Oxygenase-1 Determine the Fate of Adipose Tissue-Derived Mesenchymal Stem Cells under Stressful Conditions

“…For this purpose, the cells were preincubated with the CB 1 receptor antagonist AM-251, the CB 2 receptor antagonist AM-630, the TRPV1 antagonist capsazepine, and the GPR55 agonist O-1602. All antagonists were used at a concentration of 1 μM, which in previous studies led to interferences with CB 1 -, CB 2 - and TRPV1-dependent cannabinoid effects [ 12 , 13 , 14 , 30 , 31 , 32 ]. The same applies to the GPR55 agonist O-1602, which, at a concentration of 1 µM, has been shown to inhibit the action of the GPR55 antagonist CBD in ADMSCs [ 12 ].…”

“…In this context, studies in recent years have demonstrated a protective effect of cannabinoids on the survival of cardiovascular cells under ischemic and nutrient-poor conditions [ 9 , 10 ]. Further investigations have shown that MSCs from adipose tissue as well as MSCs from other sources express the complete endocannabinoid system [ 11 , 12 , 13 , 14 ]. The endocannabinoids as well as the phytocannabinoids cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) stimulate the migration of ADMSCs, which is considered an important function in wound healing and tissue regeneration [ 12 , 13 , 14 ].…”

Cannabinoids, their cellular receptors, and effects on the invasive phenotype of carcinoma and metastasis

“…7 However, the properties of cannabinoid molecules in the context of cancer and non-malignant cell migration, invasion, and metastasis remain poorly understood. Numerous studies report conflicting results, including be enhanced migration mediated through phosphatidylinositol 3-kinase (PI3K), 8 increased migration through mitogen-activated protein kinase (MAPK) pathways, 9 decreased migration through modulation of matrix metalloproteinase (MMP) activity 10 and decreased migration through a cannabinoid-receptor-independent mechanism. 11 Studies investigating these diverse phenomena indicate that cannabinoid signaling and its subsequent effects on cell migration and invasion are not as straightforward as would be anticipated from a single type of molecule activating one or two downstream signaling transduction cascades.…”