title: Ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney.
abstract: Bone marrow mesenchymal stem cells (MSCs) have shown great potential in cell therapy of solid organs. Approaches to improving the ability of grafted MSCs to survive and secrete paracrine factors represent one of the challenges for the further development of this novel therapy. In the present study, we designed a strategy of ex vivo pretreatment with the pineal hormone melatonin to improve survival, paracrine activity, and efficiency of MSCs. Using a rat model of acute renal failure, we showed that melatonin pretreatment strongly increased survival of MSCs after intraparenchymal injection. This effect was concomitant with overstimulation of angiogenesis, proliferation of renal cells, and accelerated recovery of renal function. To gain insight into the mechanisms involved in the effects observed in vivo, melatonin was tested in vitro on cultured MSCs. Our results show that through stimulation of specific melatonin receptors, melatonin induced an overexpression of the antioxidant enzyme catalase and superoxide dismutase-1 and increased the resistance of MSCs to hydrogen peroxide-dependent apoptosis. Compared with untreated cells, MSCs incubated with melatonin displayed a higher expression of basic fibroblast growth factor and hepatocyte growth factor. In addition, conditioned culture media from melatonin-treated MSCs stimulated tube formation by endothelial progenitor cells and proliferation of proximal tubule cells in culture. In conclusion, our results show that melatonin behaves as a preconditioning agent increasing survival, paracrine activity, and efficiency of MSCs. The use of this molecule for pretreatment of stem cells may represent a novel and safe approach to improving the beneficial effects of cell therapy of solid organs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U858, Institut de Médecine Moléculaire de Rangueil, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Mias
authors.forename: Elodie
authors.initials: E
authors.lastname: Trouche
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Seguelas
authors.forename: Fabien
authors.initials: F
authors.lastname: Calcagno
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.forename: Florence
authors.initials: F
authors.lastname: Sabatier
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Piercecchi-Marti
authors.forename: Laurent
authors.initials: L
authors.lastname: Daniel
authors.forename: Pascale
authors.initials: P
authors.lastname: Bianchi
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.forename: Philippe
authors.initials: P
authors.lastname: Bourin
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.forename: Daniel
authors.initials: D
authors.lastname: Cussac
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D006801:Humans; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008550:Melatonin / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009389:Neovascularization, Pathologic; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism
chemical_list: D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D008550:Melatonin