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Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK.
Biochem Pharmacol. 2014 Feb 01; 87(3):489-501.BP

Abstract

Migration and differentiation of mesenchymal stem cells (MSCs) are known to be involved in various regenerative processes such as bone healing. However, little is known about the pharmacotherapeutical options aiming at the mobilization and differentiation of MSCs. The present study therefore focussed on cannabinoids which have been demonstrated to exhibit tissue healing properties. Using Boyden chamber assays, the non-psychoactive phytocannabinoid cannabidiol (CBD) was found to increase the migration of adipose-derived MSCs in a time- and concentration-dependent manner. CBD-induced migration was inhibited by AM-630 (CB₂ receptor antagonist) and O-1602 (G protein-coupled receptor 55 [GRP55] agonist). Moreover, the promigratory effect of CBD was antagonized by inhibition of the p42/44 mitogen-activated protein kinase (MAPK) pathway which became activated upon CBD treatment. In line with this data, AM-630 and O-1602 attenuated CBD-induced p42/44 MAPK phosphorylation. A p42/44 MAPK-dependent promigratory effect was likewise demonstrated for the GPR55 antagonist O-1918 and the selective CB₂ receptor agonist JWH-133. Additional evidence for a functional effect of CBD on MSCs was provided by experiments demonstrating long-term stimulation with CBD to induce differentiation of MSCs into the osteoblastic lineage as evidenced by increased mineralization assessed by cresolphthalein complexone assay and enhanced activity of alkaline phosphatase. Collectively, this study demonstrates CBD to promote the migration of MSCs via activation of the CB₂ receptor and inhibition of GPR55 and to induce osteoblastic differentiation. CBD may therefore recruit MSCs to sites of calcifying tissue regeneration and subsequently support bone regeneration via an osteoanabolic action on MSCs.

Authors+Show Affiliations

Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany; Department of Cell Biology, University of Rostock, Schillingallee 69, D-18057 Rostock, Germany.Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany.Department of Cell Biology, University of Rostock, Schillingallee 69, D-18057 Rostock, Germany.Department of Cell Biology, University of Rostock, Schillingallee 69, D-18057 Rostock, Germany.Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany. Electronic address: burkhard.hinz@med.uni-rostock.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24304686

Citation

Schmuhl, Ellen, et al. "Increase of Mesenchymal Stem Cell Migration By Cannabidiol Via Activation of P42/44 MAPK." Biochemical Pharmacology, vol. 87, no. 3, 2014, pp. 489-501.
Schmuhl E, Ramer R, Salamon A, et al. Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. Biochem Pharmacol. 2014;87(3):489-501.
Schmuhl, E., Ramer, R., Salamon, A., Peters, K., & Hinz, B. (2014). Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. Biochemical Pharmacology, 87(3), 489-501. https://doi.org/10.1016/j.bcp.2013.11.016
Schmuhl E, et al. Increase of Mesenchymal Stem Cell Migration By Cannabidiol Via Activation of P42/44 MAPK. Biochem Pharmacol. 2014 Feb 1;87(3):489-501. PubMed PMID: 24304686.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. AU - Schmuhl,Ellen, AU - Ramer,Robert, AU - Salamon,Achim, AU - Peters,Kirsten, AU - Hinz,Burkhard, Y1 - 2013/12/01/ PY - 2013/08/09/received PY - 2013/11/22/revised PY - 2013/11/22/accepted PY - 2013/12/6/entrez PY - 2013/12/7/pubmed PY - 2014/3/29/medline KW - (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1.6-benzene disulfonate) KW - (6aR,10aR)-3-(1,1-dimethylbutyl)-6a-,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,-d]pyran, selective CB(2) agonist KW - 1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]benzene, selective GPR55 antagonist KW - 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, inhibitor of p42/44 MAPK activation KW - 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride, upstream inhibitor of Akt KW - 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine, kinase inhibitor, upstream inhibitor of FAK KW - 5-methyl-4-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-1,3-benzenediol, selective GPR55 agonist KW - ALP KW - AM-251 KW - AM-630 KW - CB(1) KW - CB(2) KW - Cannabidiol KW - Cannabinoid receptors KW - Differentiation KW - FAK KW - G protein-coupled receptor 55 KW - GPR55 KW - JWH-133 KW - LY-294.002 KW - MAPK KW - MSCs KW - Mesenchymal stem cells KW - Migration KW - O-1602 KW - O-1918 KW - PD98059 KW - PI3K KW - PKB KW - PP2 KW - RT-PCR KW - Scr kinase KW - TRPV1 KW - WST-1 KW - [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl) (4-methoxyphenyl)methanone], selective CB(2) receptor antagonist KW - [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], selective CB(1) receptor antagonist KW - alkaline phosphatase KW - cannabinoid receptor 1 KW - cannabinoid receptor 2 KW - focal adhesion kinase KW - mesenchymal stem cells KW - mitogen-activated protein kinase KW - phosphatidylinositol 3-kinase KW - protein kinase B/Akt KW - reverse transcriptase-polymerase chain reaction KW - sarcoma kinase KW - transient receptor potential vanilloid 1 SP - 489 EP - 501 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 87 IS - 3 N2 - Migration and differentiation of mesenchymal stem cells (MSCs) are known to be involved in various regenerative processes such as bone healing. However, little is known about the pharmacotherapeutical options aiming at the mobilization and differentiation of MSCs. The present study therefore focussed on cannabinoids which have been demonstrated to exhibit tissue healing properties. Using Boyden chamber assays, the non-psychoactive phytocannabinoid cannabidiol (CBD) was found to increase the migration of adipose-derived MSCs in a time- and concentration-dependent manner. CBD-induced migration was inhibited by AM-630 (CB₂ receptor antagonist) and O-1602 (G protein-coupled receptor 55 [GRP55] agonist). Moreover, the promigratory effect of CBD was antagonized by inhibition of the p42/44 mitogen-activated protein kinase (MAPK) pathway which became activated upon CBD treatment. In line with this data, AM-630 and O-1602 attenuated CBD-induced p42/44 MAPK phosphorylation. A p42/44 MAPK-dependent promigratory effect was likewise demonstrated for the GPR55 antagonist O-1918 and the selective CB₂ receptor agonist JWH-133. Additional evidence for a functional effect of CBD on MSCs was provided by experiments demonstrating long-term stimulation with CBD to induce differentiation of MSCs into the osteoblastic lineage as evidenced by increased mineralization assessed by cresolphthalein complexone assay and enhanced activity of alkaline phosphatase. Collectively, this study demonstrates CBD to promote the migration of MSCs via activation of the CB₂ receptor and inhibition of GPR55 and to induce osteoblastic differentiation. CBD may therefore recruit MSCs to sites of calcifying tissue regeneration and subsequently support bone regeneration via an osteoanabolic action on MSCs. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/24304686/Increase_of_mesenchymal_stem_cell_migration_by_cannabidiol_via_activation_of_p42/44_MAPK_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(13)00747-8 DB - PRIME DP - Unbound Medicine ER -