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TISSUE-SPECIFIC STEM CELLS

Ex Vivo Pretreatment with Melatonin Improves Survival, Proangiogenic/Mitogenic Activity, and Efficiency of Mesenchymal Stem Cells Injected into Ischemic Kidney

^aInstitut National de la Santé et de la Recherche Médicale, U858, Institut de Médecine Moléculaire de Rangueil, Toulouse, France;
^bFaculté des Sciences Pharmaceutiques, Université Toulouse III Paul Sabatier, Toulouse, France;
^cUnite Mixte de Recherche-S 608, Institut National de la Santé et de la Recherche Médicale, Université de la Méditerranée, Marseille, France;
^dUniversité de la Méditerranée, Marseille, France;
^eEtablissement Français du Sang, Laboratoire de Thérapie Cellulaire, Toulouse, France

Key Words. Mesenchymal stem cell • Melatonin • Survival • Angiogenesis • Therapeutic efficacy

Correspondence: Angelo Parini, M.D., Ph.D., I2MR, INSERM U858, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France. Telephone: 33-5-61-32-36-01; Fax: 33-5-62-17-25-54; e-mail: angelo.parini{at}toulouse.inserm.fr

Received November 27, 2007; accepted for publication April 28, 2008.
First published online in STEM CELLS EXPRESS   May 8, 2008.

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.

Disclosure of potential conflicts of interest is found at the end of this article.