Local irradiation induces not only homing of human Mesenchymal Stem Cells (hMSC) at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution following irradiation damages

¹ Laboratoire de Thérapie Cellulaire et Radioprotection Accidentelle, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), BP n°17, F-92262 Fontenay aux Roses CEDEX, France
² EA 1638, Laboratoire de Thérapie Cellulaire et Radioprotection Accidentelle, Faculté de Médecine Saint Antoine, Université Paris VI Pierre et Marie Curie, 27 rue de Chaligny- 75012 Paris, France
³ EA 1638, Laboratoire de Thérapie Cellulaire et Radioprotection Accidentelle, Faculté de Médecine Saint Antoine, Université Paris VI Pierre et Marie Curie, 27 rue de Chaligny- 75012 Paris, France; Service d'Hématologie et de Thérapie cellulaire, Hôpital Saint Antoine, 75012 Paris, France

^* To whom correspondence should be addressed. E-mail: alain.chapel{at}irsn.fr.

	Abstract

Background and rationale: Mesenchymal Stem Cells (MSC) have been shown to migrate to various tissues. There is little information on the fate and potential therapeutic efficacy of the reinfusion of MSC following total body irradiation (TBI). We addressed this question using human MSC (hMSC) infused IV to NOD/SCID mice submitted to total body irradiation. Further, we tested the impact of additional local irradiation superimposed to TBI, as a model of accidental irradiation. We compared additional local irradiation to one limb and to the abdomen. Material and methods: Forty NOD/SCID mice, divided in four groups (n=10 per group), were transplanted with 5.10⁶ hMSC. Group 1 was not irradiated before receiving hMSC infusion. Groups 2, 3 and 4 received TBI at a sublethal dose of 3.5 Gray, before hMSC infusion, as follows: Group 2 received TBI only; Group 3 received local irradiation to the abdomen at a dose of 4.5 Gray in addition to TBI; and Group 4 received local irradiation to the right posterior leg at 26.5 Gray in addition to TBI. Each group had its own control of 5 animals that did not receive hMSC. The animals were sacrificed 15 days after irradiation and the quantitative and spatial distribution of the hMSC was studied through PCR and immunohistology analysis. Results: Histological analysis of mouse tissues confirmed the presence of radio-induced lesions in the irradiated fields. Following their infusion into non-irradiated animals, hMSC homed at a very low level to various tissues. Human DNA accounted for engraftment of 0.06% MSC in lungs, 0.14% in bone marrow and 0.07% in quadriceps muscle. No significant hMSC engraftment was found in the brain, kidneys, liver, gut, stomach, heart, skin, muscle and peripheral blood. Total body irradiation induced an increase on engraftment levels of hMSC of 2.8 fold in the brain (p<0.05), 3 fold in the heart (p<0.05), 2.5 fold in the liver (p<0.05), 2.6 fold in bone marrow (p<0.001) and 1.7 fold in muscles (p<0.05). No increase was detected in the lungs (0.04%). Both local irradiations in addition to TBI, increased hMSC engraftment rate at the sites of local irradiation. Abdominal irradiation as compared to right leg irradiation increased hMSC engraftment in the exposed area by 2 fold in the gut (P<0.001), 2.3 fold in the liver and 9.3 fold in the spleen. Right hind leg irradiation as compared to abdominal irradiation increased hMSC engraftment in the exposed area by 5 fold in the skin (P<0.05), and 3 fold in quadriceps muscles (P<0.001). An important finding was an increase of hMSC engraftment in organs outside the fields of the local additional irradiation: following abdominal irradiation as compared to right leg irradiation, hMSC engraftment was increased by 1.8 fold in bone marrow, and 11.6 fold in lungs (P<0.05). Conversely, following right leg irradiation as compared to abdominal irradiation, hMSC engraftment was increased by 2.2 fold in the brain (P<0.05). Conclusion: This study shows that engraftment of systemically administered hMSC in NOD/SCID mice increases significantly in response to tissue injuries produced by total body irradiation with or without additional localised irradiation. Additional localised irradiation induces an increase in engraftment locally as well as at sites outside the local irradiation field, suggesting a distant (abscopal) effect of radiation damage. This work supports the use of MSC infusion to repair damaged tissues following accidental irradiation and possibly in patients submitted to controlled radiotherapy for the treatment of solid tumors.

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