Abstract

Regenerative activity in tissues of mesenchymal origin depends on the migratory potential of mesenchymal stem cells (MSC). 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). Using Boyden chamber assays, the FAAH inhibitors URB597 and arachidonoyl serotonin were found to increase the migration of human adipose-derived MSC. LC-MS analyses revealed increased levels of all 4 aforementioned FAAH substrates in MSC incubated with either FAAH inhibitor. Following addition to MSC, 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 mitogen-activated protein kinases (MAPK) as well as to cytosol-to-nucleus translocation of the transcription factor peroxisome proliferator-activated receptor α (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, this data demonstrate FAAH inhibitors and substrates to cause p42/44 MAPK phosphorylation, which subsequently activates PPARα to confer increased migration of MSC. This novel pathway may be involved in regenerative effects of endocannabinoids whose degradation could be a target of pharmacological intervention by FAAH inhibitors.