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IRSN, Institut de radioprotection et de sûreté nucléaire

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Enhancing Nuclear Safety


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CELL THERAPY, A NEW APPROACH TO MULTIORGAN FAILURE SYNDROME FOLLOWING SEVERE IRRADIATION.

A. Chapel, M. Bensidhoum, J-M. Bertho, J. Frick1, C. Demarquay, C Mazurier, S.François, M. Mouiseddine,S.Bouchet, M. Lopez ,N. Dudoignon, J Aigueperse, C Gorin, P Gourmelon and D Thierry, IRPA 11, 24-28/05/2004, Madrid (Spain).

Summary

Recent work has suggested that hematopoietic and mesenchymal cell therapy could be a choice therapy in the context of a radiation accident (Bertho 2002, Chapel 2003). We hypothesize that using mesenchymal stem cells as a source of cells able to home in various tissues and to repair the damage induced by radiation could be an interesting strategy. We therefore investigated the potential of combining the ex-vivo expansion of haematopoitic cells with mesenchymal stem cells infusion for the treatment of acute radiation syndrome. For this, in a non-human primate model, haematopoietic stem cells and mesenchymal stem cells were taken from bone marrow and expanded. A part of mesenchymal stem cells were transduced with the gene encoding for the green fluorescent protein, in order to track them in the organism. In order to mimic accidental settings, 9 animals were total body irradiated 8 Gy with a neutron/gamma source. The animals were treated using expanded haematopoietic stem cells and/or mesenchymal stem cells. Depending on the neutron/gamma ratio, an acute radiation sickness of different deepness but of similar nature could be produced. The animals were studied for their clinical, biochemical, cellular and molecular biology parameters. Results evidenced that animals might benefit from the treatment since a better haematopoietic recovery was observed and since MSC were found in injured muscle, skin and bone marrow of the treated animals. Global repair process was observed in various tissues. In order to determine factors involved in MSC recruitment, migration, and homing kinetics, human MSC were injected following global or local (abdomen) irradiations to an immunotolerant NOD /SCID mouse model. We have tracked human MSCs through the use of real time PCR assay that specifically amplify human genes. Systemic delivery of human bone marrow expanded MSCs into sublethally irradiated NOD/SCID mice recipients resulted in homing to liver, bone , bone marrow, gut , hearth, kidney, brain, lung, stomach 15 days post treatment. Human MSCs were found for up to 3 months in gut, lung, bone marrow, and heart. After abdominal radiation exposure human MSCs engrafted preferentially in the abdomen at 15 day. By contrast human MSCs were found only in small quantities in other body areas. These observations support our hypothesis that MSCs can be recruited to sites of radiation injury. Finally, in the same model, following total body irradiation, combined human hematopoietic and/or mesenchymal subpopulations of cells were injected in order to evidence the role of each cell type in the treatment of the various radiation induced tissue aplasias.
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