Inhibition of FAAH confers increased stem cell migration via PPARα.
Regenerative activity in tissues of mesenchymal origin depends on the migratory potential of mesenchymal stem cells (MSCs). The present study focused on inhibitors of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the degradation of endocannabinoids (anandamide, 2-arachidonoylglycerol) and endocannabinoid-like substances (N-oleoylethanolamine, N-palmitoylethanolamine). Boyden chamber assays, the FAAH inhibitors, URB597 and arachidonoyl serotonin (AA-5HT), were found to increase the migration of human adipose-derived MSCs. LC-MS analyses revealed increased levels of all four aforementioned FAAH substrates in MSCs incubated with either FAAH inhibitor. Following addition to MSCs, all FAAH substrates mimicked the promigratory action of FAAH inhibitors. Promigratory effects of FAAH inhibitors and substrates were causally linked to activation of p42/44 MAPKs, as well as to cytosol-to-nucleus translocation of the transcription factor, PPARα. Whereas PPARα activation by FAAH inhibitors and substrates became reversed upon inhibition of p42/44 MAPK activation, a blockade of PPARα left p42/44 MAPK phosphorylation unaltered. Collectively, these data demonstrate FAAH inhibitors and substrates to cause p42/44 MAPK phosphorylation, which subsequently activates PPARα to confer increased migration of MSCs. This novel pathway may be involved in regenerative effects of endocannabinoids whose degradation could be a target of pharmacological intervention by FAAH inhibitors.
Institute of Toxicology and Pharmacology, Rostock University Medical Center, D-18057 Rostock, Germany Department of Cell Biology, Rostock University Medical Center, D-18057 Rostock, Germany.
Yvonne
Y
Wollank
Institute of Toxicology and Pharmacology, Rostock University Medical Center, D-18057 Rostock, Germany.
Robert
R
Ramer
Institute of Toxicology and Pharmacology, Rostock University Medical Center, D-18057 Rostock, Germany.
Igor
I
Ivanov
Department of Cell Biology, Rostock University Medical Center, D-18057 Rostock, Germany.
Achim
A
Salamon
Department of Cell Biology, Rostock University Medical Center, D-18057 Rostock, Germany.
Kirsten
K
Peters
Institute of Toxicology and Pharmacology, Rostock University Medical Center, D-18057 Rostock, Germany.
Burkhard
B
Hinz
D000273:Adipose Tissue / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001095:Arachidonic Acids / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009829:Oleic Acids / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism*; D010169:Palmitic Acids / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000577:Amides; D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D005989:Glycerides; D009829:Oleic Acids; D047493:PPAR alpha; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D012701:Serotonin; D000099252:Fatty Acid Amide Hydrolases; C114007:arachidonoylserotonin; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C033595:N-oleoylethanolamine; C005958:palmidrol; C094503:glyceryl 2-arachidonate; C078814:anandamide
endocannabinoids; fatty acid amide hydrolase inhibitors; mesenchymal stem cells; peroxisome proliferator-activated receptor α