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First published online May 8, 2008
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Submitted on November 27, 2007
Accepted on April 28, 2008

TISSUE-SPECIFIC STEM CELLS

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

Céline Mias 1, Elodie Trouche 1, Marie Hélène Seguelas 1, Fabien Calcagno 2, Françoise Dignat-George 2, Florence Sabatier 2, Marie Dominique Piercecchi-Marti 2, Laurent Daniel 3, Pascale Bianchi 1, Denis Calise 1, Philippe Bourin 4, Angelo Parini 5*, Daniel Cussac 5

1 INSERM, U858, Institut de Médecine Moléculaire de Rangueil, I2MR, Toulouse, France
2 UMR-S 608 INSERM- Université de la Méditerranée, Marseille, France
3 Université de la Méditerranée, EA 3281, Marseille, France
4 EFS, Laboratoire de thérapie cellulaire, Toulouse, France
5 INSERM, U858, Institut de Médecine Moléculaire de Rangueil, I2MR, Toulouse, France; Université Toulouse III Paul Sabatier, Faculté des sciences pharmaceutiques, Toulouse, France

* To whom correspondence should be addressed. E-mail: angelo.parini{at}toulouse.inserm.fr.


  Abstract

Bone marrow mesenchymal stem cells (MSCs) have shown a large potential in cell therapy of solid organs. Approaches to improve the ability of grafted MSCs to survive and secrete paracrine factors represent one of the challenges for the further development of these novel therapies. 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 to overstimulation of angiogenesis, proliferation of renal cells and accelerated recovery of renal function.

To gain insight on 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 MT receptors, melatonin induced an overexpression of the antioxidant enzyme catalase and superoxyde dismutase-1 and increased the resistance of MSCs to hydrogen peroxide-dependent apoptosis. As compared to untreated cells, MSCs incubated with melatonin displayed a higher expression of b-FGF and HGF. 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 for improving the beneficial effects of cell therapy of solid organs.

______________________________________________________________________________

Author contributions: C.M.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing; E.T.: Collection and/or assembly of data, Data analysis and interpretation; M.S.: Collection and/or assembly of data; F.C.: Collection and/or assembly of data, Data analysis and interpretation; F.D.: Conception and design, Data analysis and interpretation, Final approval of manuscript; F.S.: Conception and design, Data analysis and interpretation, Final approval of manuscript; M.P.: Collection and/or assembly of data, Data analysis and interpretation; L.D.: Data analysis and interpretation; P.B.: Conception and design; D.C.: Collection and/or assembly of data, Data analysis and interpretation; P.B.: Conception and design, Provision of study material or patients; A.P.: Conception and design, Data analysis and interpretation, Manuscript writing, Final approval of manuscript, Financial support; D.C.: Conception and design, Data analysis and interpretation, Manuscript writing, Final approval of manuscript.

 Key Words. Mesenchymal stem cell, melatonin, survival, angiogenesis, therapeutic efficacy






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